Psoriasis: Gordon KB

Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordon KB, Gottlieb A, Koo JY, Lebwohl M, Lim HW, Van Voorhees AS, Beutner KR, Bhushan R, Anonymous00035. · Baylor University Medical Center, Dallas, Texas, USA. · J Am Acad Dermatol. · Pubmed #19217694 No free full text.

Abstract: Psoriasis is a common, chronic, inflammatory, multi-system disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In this third of 6 sections of the guidelines of care for psoriasis, we discuss the use of topical medications for the treatment of psoriasis. The majority of patients with psoriasis have limited disease (<5% body surface area involvement) and can be treated with topical agents, which generally provide a high efficacy-to-safety ratio. Topical agents may also be used adjunctively for patients with more extensive psoriasis undergoing therapy with either ultraviolet light, systemic or biologic medications. However, the use of topical agents as monotherapy in the setting of extensive disease or in the setting of limited, but recalcitrant, disease is not routinely recommended. Treatment should be tailored to meet individual patients' needs. We will discuss the efficacy and safety of as well as offer recommendations for the use of topical corticosteroids, vitamin D analogues, tazarotene, tacrolimus, pimecrolimus, emollients, salicylic acid, anthralin, coal tar, as well as combination therapy.

Gottlieb A, Korman NJ, Gordon KB, Feldman SR, Lebwohl M, Koo JY, Van Voorhees AS, Elmets CA, Leonardi CL, Beutner KR, Bhushan R, Menter A. · Department of Dermatology, Tufts-New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA. · J Am Acad Dermatol. · Pubmed #18423261 No free full text.

Abstract: Psoriasis is a common, chronic, inflammatory, multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In this second of 5 sections of the guidelines of care for psoriasis, we give an overview of psoriatic arthritis including its cardinal clinical features, pathogenesis, prognosis, classification, assessment tools used to evaluate psoriatic arthritis, and the approach to treatment. Although patients with mild to moderate psoriatic arthritis may be treated with nonsteroidal anti-inflammatory drugs and/or intra-articular steroid injections, the use of disease-modifying antirheumatic drugs, particularly methotrexate, along with the biologic agents, are considered the standard of care in patients with more significant psoriatic arthritis. We will discuss the use of disease-modifying antirheumatic drugs and the biologic therapies in the treatment of patients with moderate to severe psoriatic arthritis.

Menter A, Gottlieb A, Feldman SR, Van Voorhees AS, Leonardi CL, Gordon KB, Lebwohl M, Koo JY, Elmets CA, Korman NJ, Beutner KR, Bhushan R. · Baylor University Medical Center, Dallas, Texas, USA. · J Am Acad Dermatol. · Pubmed #18423260 No free full text.

Abstract: Psoriasis is a common, chronic, inflammatory, multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In this first of 5 sections of the guidelines of care for psoriasis, we discuss the classification of psoriasis; associated comorbidities including autoimmune diseases, cardiovascular risk, psychiatric/psychologic issues, and cancer risk; along with assessment tools for skin disease and quality-of-life issues. Finally, we will discuss the safety and efficacy of the biologic treatments used to treat patients with psoriasis.

Gordon KB, Feldman SR, Koo JY, Menter A, Rolstad T, Krueger G. · No affiliation provided · Arch Dermatol. · Pubmed #15655149 No free full text.

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Gordon KB. · No affiliation provided · Arch Dermatol. · Pubmed #15655148 No free full text.

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Friedewald VE, Cather JC, Gelfand JM, Gordon KB, Gibbons GH, Grundy SM, Jarratt MT, Krueger JG, Ridker PM, Stone N, Roberts WC. · Department of Internal Medicine, The University of Texas Medical School at Houston, Houston, Texas, USA. · Am J Cardiol. · Pubmed #19064017 No free full text.

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Langley RG, Gordon KB. · Division of Dermatology, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada. · J Drugs Dermatol. · Pubmed #18189060 No free full text.

Abstract: BACKGROUND: The efficacy of biologic agents to treat psoriasis has been established in well-designed clinical trials. The primary endpoint is usually a 75% reduction from the baseline Psoriasis Area and Severity Index, stressing acute control of symptoms. Another important endpoint is remission, or duration of response off therapy, which reduces exposure to immunosuppressive agents and potentially lowers costs. METHODS: We searched the literature for randomized controlled clinical trials of remission with biologic agents. RESULTS AND CONCLUSIONS: Among approved biologic agents, alefacept produced the longest posttreatment clinical benefits in responders (7 to 8.6 months after a 12-week course), followed by infliximab (4.7 months after a 6-week, 3-dose induction period), etanercept (2.8 to 3.5 months after 12 weeks of therapy), and efalizumab (2.8 months after 24 weeks of therapy). Long-term response to infliximab in some patients may be limited by neutralizing antibodies. Additional data on adalimumab are needed.

Nickoloff BJ, Bonish BK, Marble DJ, Schriedel KA, DiPietro LA, Gordon KB, Lingen MW. · Department of Pathology, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, Illinois 60153, USA. · J Investig Dermatol Symp Proc. · Pubmed #17069007 No free full text.

Abstract: Following injury, skin establishes a balance between too little inflammation increasing risk of infection, and excessive inflammation contributing to delayed wound healing and scarring. Mounting evidence indicates both initiation and termination of inflammation involve active mechanisms. Not only does inflammation itself seem to be a paradox because inflammatory responses are both essential and potentially detrimental, but one chronic inflammatory skin disease (e.g. psoriasis) presents additional paradoxes. While plaques share several factors with wound healing, two understudied and puzzling aspects include why do not inflamed plaques more frequently transform?; and why do not plaques result in scarring? To get at these questions, we review responses involved in wound repair. Oral mucosa was probed because, like fetal skin, wound repair is characterized by its rapidity, low inflammation, and scarless resolution. Active roles for macrophages as both initiators and terminators of inflammation are highlighted. Therapeutic implications are discussed regarding psoriasis and pyoderma gangrenosum. Based on biochemical and immunohistochemical considerations linking psoriatic plaques to hard palate, a novel metaplastic model is presented. We hypothesize saliva and chronic trauma contribute to a constitutive epithelial program where keratinocyte proliferation is more intense prior to differentiation, accompanied by keratin 16 expression in hard palate, thereby resembling plaques. Rather than viewing psoriasis as a nonspecific response to inflammation, we postulate a metaplastic switch by which prepsoriatic skin is converted to a distinct adult tissue type resembling hard palate. In summary, many lessons can be learned by focusing on complex processes involved in regulation of inflammation, tissue repair, and remodeling.

Pariser DM, Gordon KB, Papp KA, Leonardi CL, Kwon P, Compton PG, Rundle AC, Walicke PA, Lebwohl M. · Department of Dermatology, Eastern Virginia Medical School, Norfolk, VA, USA. · J Cutan Med Surg. · Pubmed #16699904 No free full text.

Abstract: BACKGROUND: Effective psoriasis therapies are needed for long-term symptom control. OBJECTIVE: Assess efalizumab (Raptiva) efficacy in a large cohort of psoriasis patients. METHODS: Data from three Phase III, randomized, double-blind, parallel-group, placebo-controlled, multicenter studies were pooled. Patients (n = 1,651) with moderate to severe plaque psoriasis received 12 weeks of subcutaneous efalizumab 1 or 2 mg/kg/wk or placebo. RESULTS: All efficacy measures reached statistical significance within each of the individual studies (p < 0.001) and overall. More efalizumab-treated patients achieved > or = 75% and > or = 50% Psoriasis Area and Severity Index (PASI) improvement at week 12 than did placebo-treated patients (27.8% vs 3.8% [p < 0.001] and 56.1% vs 14.6% [p < 0.001], respectively). Significant PASI improvements occurred as early as week 2 (12.5% vs 7.9%, p =0.0001). Adverse events were generally mild to moderate. CONCLUSION: Efalizumab resulted in early and significant improvement for all efficacy endpoints and was well tolerated in patients with moderate to severe chronic plaque psoriasis.

Gordon KB, Ruderman EM. · Division of Dermatology, Evanston Northwestern Healthcare, Skokie, Illinois 60077, USA. · J Am Acad Dermatol. · Pubmed #16488334 No free full text.

Abstract: Psoriatic arthritis is a common inflammatory arthritis associated with psoriasis, occurring in 5% to 40% of patients with cutaneous disease. Recently, there has been an increased appreciation of the need to use an integrated approach to these 2 diseases, considering both entities when determining therapeutic choices. In this review, the available therapeutic options for psoriatic arthritis are considered, along with the potential benefit that these medications may have for cutaneous psoriasis. Finally, a conceptual model for the therapy of psoriasis and psoriatic arthritis, the Four Quadrant Model, is presented as a simplified framework to use when considering treatment for psoriatic disease.

Langley RG, Carey WP, Rafal ES, Tyring SK, Caro I, Wang X, Wetherill G, Gordon KB. · Dalhousie University, Halifax, Nova Scotia, Canada. · Clin Ther. · Pubmed #16291408 No free full text.

Abstract: BACKGROUND: Because many therapies for psoriasis disrupt the normal inflammatory cascade and could theoretically impair the body's ability to respond to external pathogens, a possible increase in the incidence of infection is a concern with any new psoriasis therapy that affects the immune system. Efalizumab is a biologic therapy targeted to inhibit T cells. Its efficacy has been shown in clinical trials encompassing >3500 patients with psoriasis. OBJECTIVES: The aims of this article were to review the incidence of infection observed in efalizumab-treated patients during 12-week, Phase III clinical trials, compare the incidence rate with that in patients receiving placebo, and evaluate the incidence of infection observed in patients with extended (>12-week) efalizumab use. METHODS: Adverse events (AEs) of infection were tabulated from a pooled data set of 2335 patients enrolled to receive 12 weeks of subcutaneous (SC) efalizumab 1 or 2 mg/kg . wk or placebo in 4 randomized, double-blind, placebo-controlled, Phase III efalizumab clinical studies. The incidence of infection was further evaluated using pooled data from 1115 patients who received up to 24 weeks of efalizumab therapy during 5 clinical trials with treatment extension arms and from 170 patients who received up to 108 weeks (27 months) of continuous therapy in an open-label, Phase III efalizumab trial of 36 months' total duration. RESULTS: The incidence and severity of AEs of infection during 12 weeks of efalizumab therapy were comparable to those observed in patients receiving placebo (overall, 28.6% vs 26.3%). Infections did not appear to increase with extended therapy of up to 27 months. Serious infections requiring hospitalization occurred in 1.1% of efalizumab-treated patients. CONCLUSION: The present review of the available Phase III clinical trial suggests that efalizumab is not associated with an increased risk for infection in patients receiving initial or long-term (27-month) treatment for moderate to severe chronic plaque psoriasis.

Gordon KB, Valentine J. · Division of Dermatology, Loyola University Medical Center, Maywood, IL 60153, USA. · J Cutan Med Surg. · Pubmed #15668749 No free full text.

Abstract: With the completion of several phase 2 and phase 3 clinical studies, the efficacy and tolerability of alefacept in patients with chronic plaque psoriasis is now well studied. The majority of patients treated with a single course of intravenous or intramuscular alefacept experienced a clinically meaningful response. The efficacy of alefacept correlated with its ability to selectively target and reduce the number of pathogenic memory T cells. A second course of alefacept resulted in further clinical improvement, with increasing response rates and prolonged response duration following treatment cessation. Subpopulation analyses demonstrated that alefacept is effective in a broad spectrum of patients with psoriasis, regardless of disease severity, history of and response to prior antipsoriatic treatment, or whether patients are refractory to or have contraindications to other systemic psoriasis therapies or phototherapy.

Mehlis S, Gordon KB. · Department of Dermatology, Northwestern University Medical School, 675 N. St. Clair Street, Chicago, IL 60611, USA. · Dermatol Clin. · Pubmed #15450333 No free full text.

Abstract: Traditional systemic therapy for psoriasis is limited by either lack of efficacy or the long-term side effect profile of the medications used. Newer information about the pathophysiology of the disease has led to new perspectives on developing novel techniques for attacking psoriasis. This article discusses the pathogenesis of psoriasis, looks at the immunologic factors that contribute to forming a psoriatic plaque, reviews how novel biologic therapies are made, and explores how biologics can target each of these specific parts of the immunologic cascade.

Patel T, Gordon KB. · Department of Medicine, Division of Dermatology, Loyola University, Stritch School of Medicine, Maywood, Illinois 60153, USA. · Dermatol Ther. · Pubmed #15379777 No free full text.

Abstract: The next generation of targeted biologic therapies for psoriasis will either be directed against new protein targets or improve on the efficacy, safety, or convenience of medications available for an already validated area in the immune response. Adalimumab is a fully human monoclonal antibody directed against tumor necrosis factor-alpha, a central cytokine in the immune response in psoriasis that has already been shown to be an effective target for therapy. This medication is approved by the US Food and Drug Administration (USFDA) for the treatment of rheumatoid arthritis. Early phrase II studies with adalimumab have shown excellent efficacy for psoriasis with either weekly or every other week subcutaneous injection. Moreover, the safety and tolerability of adalimumab in large clinical studies of rheumatoid arthritis have shown good results. Thus, adalimumab shows significant promise for the therapy of psoriasis in the future.

Gordon KB, McCormick TS. · Department of Medicine, Division of Dermatology, Loyola University, Stritch School of Medicine, Maywood, IL 60153, USA. · Skinmed. · Pubmed #14673261 No free full text.

Abstract: Over the past three decades, laboratory and clinical research findings have shown that T cells are the primary mediators of psoriasis pathogenesis and that psoriasis can be treated by eliminating these T cells or interfering with their activation or activity. Based on these observations, many new biologic therapies to treat psoriasis are now in development. These agents, developed primarily through recombinant DNA techniques, are designed to target T cells and the immunologic cascade associated with their activation. Four basic strategic approaches that focus on the steps involved in the immunopathology of psoriasis are: 1) elimination of the pathogenic T cells; 2) inhibition of T-cell activation, proliferation, and migration; 3) immune deviation to down-regulate the type 1 (TH1) response predominant in psoriasis; and 4) blockade of cytokine production. The goal of these new therapies is to improve the treatment of psoriasis, particularly moderate to severe disease, with agents that are well tolerated and safe for long-term use.

Mehlis SL, Gordon KB. · Division of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. · J Am Acad Dermatol. · Pubmed #12894125 No free full text.

Abstract: In this review, we will discuss the immunological basis for psoriasis with special emphasis on the role of effector T cells. With the understanding of this immunologic process, we will present a model for the development of targeted immune response modifiers, termed biologic immunotherapies, and their potential role for the benefit of patients with psoriasis.

McClure SL, Valentine J, Gordon KB. · Department of Dermatology, Northwestern University Medical School, Chicago, Illinois 60611, USA. · Drug Saf. · Pubmed #12381213 No free full text.

Abstract: Psoriasis is a chronic, debilitating skin condition that affects millions of people and is attributed to both genetic and environmental factors. Topical therapy is generally considered to be the first-line treatment of psoriasis. However, many patients do not respond to topical therapy or have disease so extensive that topical therapy is not practical. For these patients, systemic therapy is indicated. Presently, there are four available systemic treatments, psoralen with ultraviolet A (PUVA), methotrexate, oral retinoids (acitretin), and cyclosporin. Unfortunately, all of these treatments have significant potential adverse effects. PUVA may acutely cause nausea, pruritus and sunburn. More chronic and concerning is the development of PUVA lentigines, ocular complications and skin cancer. Non-melanoma skin cancer has been directly linked to PUVA; however, the association with melonoma is more elusive. Methotrexate use most notably carries the risk of hepatic fibrosis and cirrhosis, which is not always evident on liver function tests. Other more rare, but potentially life-threatening adverse effects include pancytopenia, lymphoproliferative disorders and acute pneumonitis. The addition of folic acid may help to reduce the risk of increasing liver enzymes and haematological toxicity seen in those taking methotrexate. Both methotrexate and oral retinoids are teratogenic and should never be used in pregnancy. Oral retinoids are probably the least effective available systemic medication for the treatment of plaque psoriasis. The effects are improved with the addition of other systemic therapies. Acitretin has replaced the formerly used etretinate primarily because of the significantly shorter half-life. The adverse effects are generally mild and reversible, making the drug fairly safe for long-term use. The most commonly seen adverse effects include elevated serum lipids, generalised xerosis and alopecia. Bony abnormalities, while somewhat controversial, have also been described and include diffuse idiopathic skeletal hyperostosis, skeletal calcifications and osteoporosis. Cyclosporin is the most recently approved systemic medication for plaque psoriasis. The nephrotoxicity associated with the use of cyclosporin can be minimised when used in lower doses and for a limited duration. Hypertension is usually mild and can be seen in up to about one-third of patients receiving long-term therapy. Cutaneous and internal malignancies have also been reported with cyclosporin and tend to be correlated with duration of treatment. In this review, we will examine the potential adverse effects with these US Food and Drug Administration-approved treatments in adults, with specific emphasis on the controversies that surround long-term therapy with these agents and their cumulative adverse effects.

Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y, Li S, Dooley LT, Gordon KB, Anonymous00034. · Saint Louis University Medical School, St Louis, MO, USA. · Lancet. · Pubmed #18486739 No free full text.

Abstract: BACKGROUND: Interleukins 12 and 23 have important roles in the pathophysiology of psoriasis. We assessed ustekinumab, a human monoclonal antibody directed against these cytokines, for the treatment of psoriasis. METHODS: In this phase III, parallel, double-blind, placebo-controlled study, 766 patients with moderate-to-severe psoriasis were randomly assigned to receive ustekinumab 45 mg (n=255) or 90 mg (n=256) at weeks 0 and 4 and then every 12 weeks; or placebo (n=255) at weeks 0 and 4, with subsequent crossover to ustekinumab at week 12. Patients who were initially randomised to receive ustekinumab at week 0 who achieved long-term response (at least 75% improvement in psoriasis area and severity index [PASI 75] at weeks 28 and 40) were re-randomised at week 40 to maintenance ustekinumab or withdrawal from treatment until loss of response. Both randomisations were done with a minimisation method via a centralised interactive voice response system. The primary endpoint was the proportion of patients achieving PASI 75 at week 12. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00267969. FINDINGS: All randomised patients were included in the efficacy analysis. 171 (67.1%) patients receiving ustekinumab 45 mg, 170 (66.4%) receiving ustekinumab 90 mg, and eight (3.1%) receiving placebo achieved PASI 75 at week 12 (difference in response rate vs placebo 63.9%, 95% CI 57.8-70.1, p<0.0001 for 45 mg and 63.3%, 57.1-69.4, p<0.0001 for 90 mg). At week 40, long-term response had been achieved by 150 patients in the 45 mg group and 172 patients in the 90 mg group. Of these, 162 patients were randomly assigned to maintenance ustekinumab and 160 to withdrawal. PASI 75 response was better maintained to at least 1 year in those receiving maintenance ustekinumab than in those withdrawn from treatment at week 40 (p<0.0001 by log-rank test). During the placebo-controlled phase, adverse events occurred in 278 (54.5%) of the 510 patients receiving ustekinumab and 123 (48.2%) of the 255 receiving placebo. Serious adverse events occurred in six (1.2%) of 510 patients receiving ustekinumab and in two (0.8%) of 255 receiving placebo in this phase. The pattern of adverse events was much the same in the placebo crossover and randomised withdrawal phases as it was in the placebo-controlled phase. INTERPRETATION: Ustekinumab seems to be efficacious for the treatment of moderate-to-severe psoriasis; dosing every 12 weeks maintains efficacy for at least a year in most patients.

Kimball AB, Gordon KB, Langley RG, Menter A, Chartash EK, Valdes J, Anonymous00301. · Clinical Unit for Research Trials in Skin (CURTIS), Massachusetts General and Brigham and Women's Hospitals, Harvard Medical School, 50 Staniford St, No. 246, Boston, MA 02114, USA. · Arch Dermatol. · Pubmed #18283176 links to  free full text

Abstract: OBJECTIVE: To investigate the efficacy and safety of ABT-874, an interleukin 12/23 monoclonal antibody, in psoriasis. DESIGN: Phase 2, 12-week, multicenter, randomized, double-blind, placebo-controlled trial. SETTING: Outpatient dermatology clinics. Patients One hundred eighty patients with clinically stable moderate to severe chronic plaque psoriasis. Interventions Patients were randomized in groups of 30 to receive 1 of 6 treatments with ABT-874 provided as a subcutaneous injection: one 200-mg dose at week 0; 100 mg every other week for 12 weeks; 200 mg weekly for 4 weeks; 200 mg every other week for 12 weeks; 200 mg weekly for 12 weeks; or placebo. Main Outcome Measure At least a 75% reduction in the Psoriasis Area and Severity Index. RESULTS: The percentage of patients achieving a 75% reduction in the Psoriasis Area and Severity Index at week 12 was statistically significantly greater in all of the ABT-874 treatment groups than in the placebo group (200 mg once, 63% [19 of 30]; 100 mg every other week for 12 weeks, 93% [28 of 30]; 200 mg weekly for 4 weeks, 90% [27 of 30]; 200 mg every other week for 12 weeks, 93% [28 of 30]; 200 mg weekly for 12 weeks, 90% [27 of 30]; placebo, 3% [1 of 30]; P < .001). Treatment with ABT-874 was well tolerated. The most common adverse event was injection-site reaction, and the most common infectious adverse events were nasopharyngitis and upper respiratory tract infection. There were no serious infectious adverse events. CONCLUSIONS: ABT-874, an interleukin 12/23 monoclonal antibody, was highly effective and well tolerated in the treatment of psoriasis. Longer-term studies are required to confirm these findings.

Revicki DA, Willian MK, Menter A, Gordon KB, Kimball AB, Leonardi CL, Langley RG, Kimel M, Okun M. · Center for Health Outcomes Research, United BioSource Corporation, 7101 Wisconsin Avenue, Bethesda, MD 20814, USA. · J Dermatolog Treat. · Pubmed #18058494 No free full text.

Abstract: OBJECTIVE: The effect of adalimumab on patient-reported outcomes (PROs) was evaluated in patients with moderate to severe psoriasis during the initial 16-week, double-blind period of a 52-week, Phase III, multicenter trial. METHODS: Patients were randomized to placebo or adalimumab 80 mg at Week 0 and 40 mg every other week from Week 1 to Week 15. PROs were evaluated throughout the study and included the Dermatology Life Quality Index (DLQI), the Short Form 36 Health Survey (SF-36), the Work Productivity and Activity Impairment Questionnaire-Specific Health Problem (WPAI-SHP), and several patient-rated symptom scales. RESULTS: The adalimumab-treated group reported significantly greater improvements in DLQI total score (p<0.001), SF-36 Physical Component Summary score (p<0.001), and Mental Component Summary score (p<0.001) compared with the placebo-treated group over 16 weeks. Significant differences, favoring adalimumab, were also seen for the DLQI subscale scores (p < 0.001); SF-36 scale scores (p<0.001); WPAI-SHP work impairment (p<0.001), activity limitation (p<0.001), and overall work impairment scores (p<0.001); patient's global assessment of disease severity (p<0.001), psoriasis pain (p<0.001), and psoriasis-related pruritus (p = 0.002). CONCLUSION: Adalimumab was efficacious in improving dermatology-specific and general health-related quality of life, work and activity limitations, and psoriasis-related symptoms in patients with moderate to severe psoriasis over a 16-week period.

Marble DJ, Gordon KB, Nickoloff BJ. · Department of Medicine, Division of Dermatology, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL 60153, United States. · J Dermatol Sci. · Pubmed #17689932 links to  free full text

Abstract: BACKGROUND: The cytokine network theory for psoriasis postulates a key role for TNFalpha in mediating inflammation and altered epidermal differentiation. OBJECTIVE: This study defines responses following administration of adalimumab, a TNFalpha inhibitor, in pre-psoriatic skin (PN) and lesional psoriatic plaques (PP) skin. METHODS: PN and PP skin before and after treatment were biopsied at days 2, 7, 28 and 84 (n=6 different patients). Cryosections were immunohistochemically stained to detect TNFalpha and other relevant markers in epidermal and dermal compartments. Detection of apoptosis utilized antibody specific for activated caspase 3. Semiquantitative assessments and statistical analysis was performed for each staining profile. RESULTS: TNFalpha+ cells were increased in PP skin. PP skin was also characterized by a four-fold increase in number of CD68+ macrophages as well as eight-fold increase in CD11c+ dermal dendritic cells (DCs) compared to PN skin. By two-color immunofluorescence staining, both CD68+ cells as well as CD11c+ cells expressed TNFalpha. Following initiation of adalimumab therapy, CD11c+ cells, significantly decreased in PP skin at days 7, 28, and 84, while CD68+ and CD14+ cells decreased at days 28 and 84. Other markers for DCs (CD83, CD86) showed decreases at days 7, 28, and 84. Reduction in DCs, macrophages or T cells was not accompanied by increased activated caspase 3-positive cells. When a keratinocyte terminal differentiation marker was examined, adalimumab triggered rapid restoration of loricrin expression (beginning on day 2), with loss of aberrant differentiation marker, keratin 17 (K17). CONCLUSION: Adalimumab impacts dermal-based immunocytes, and the epidermal compartment also responds by restoration of normal differentiation without detectable apoptosis.

Tyring S, Gordon KB, Poulin Y, Langley RG, Gottlieb AB, Dunn M, Jahreis A. · Department of Dermatology, The University of Texas Health Center at Houston, 6655 Travis, Suite 120, Houston, TX 77030, and Evanston Northwest Healthcare, Skokie, IL, USA. · Arch Dermatol. · Pubmed #17576937 links to  free full text

Abstract: OBJECTIVE: To evaluate the safety and efficacy of long-term treatment of psoriasis with etanercept, 50 mg twice weekly. DESIGN, SETTING, AND PATIENTS: A phase 3, randomized, double-blind trial with an open-label extension. A total of 618 adult patients with moderate to severe plaque psoriasis were studied at 39 medical centers in the United States and Canada from May 23, 2003, through June 22, 2005. INTERVENTIONS: Patients were randomized to receive placebo or etanercept for 12 weeks. Beginning with week 13, all patients (N=591) received etanercept. MAIN OUTCOME MEASURES: Exposure-adjusted adverse event rates were calculated. Efficacy measures included efficacy and patient global assessment of psoriasis. RESULTS: Exposure-adjusted rates of adverse events, serious adverse events, infections, and serious infections were similar for placebo and etanercept treatments. Nonneutralizing antibodies to etanercept, observed in 18.3% of patients, had no apparent effect on safety or efficacy. Patients responded within 2 weeks to etanercept, with statistically significant differences in the Psoriasis Area and Severity Index and Dermatology Life Quality Index between the etanercept and placebo groups at week 12. At week 24, after 12 weeks of open-label etanercept treatment, patients in the original placebo group had clinical benefits comparable to those of patients in the original etanercept group. As both groups progressed through the open-label period, the Psoriasis Area and Severity Index response peaked at week 48. At week 96, 51.6% of the original placebo-treated patients and 51.1% of the original etanercept-treated patients had improvements from baseline in the Psoriasis Area and Severity Index of at least 75%. CONCLUSIONS: Extended exposure to 50 mg of etanercept twice weekly resulted in exposure-adjusted rates of adverse events and infections similar to those in patients receiving placebo. Improvements in physician- and patient-reported measures of psoriasis severity were observed for up to 96 weeks of continuous etanercept therapy. Trial Registration clinicaltrials.gov Identifier NCT00111449.

Papp KA, Bressinck R, Fretzin S, Goffe B, Kempers S, Gordon KB, Caro I, Walicke PA, Wang X, Menter A, Anonymous00100. · Probity Medical Research, Waterloo, Ontario, Canada. · Int J Dermatol. · Pubmed #16700803 No free full text.

Abstract: BACKGROUND: To provide safety data for efalizumab, a recombinant humanized monoclonal IgG(1) antibody, in adults with chronic plaque psoriasis. METHODS: A 12-week, Phase IIIb, randomized, double-blind, parallel-group, placebo-controlled trial. At 58 study sites in the USA and Canada, 686 patients with moderate to severe chronic plaque psoriasis received an initial conditioning dose of efalizumab 0.7 mg/kg subcutaneously (SC) followed by either 11 weekly doses of efalizumab 1 mg/kg SC or matching placebo. Main outcome measures were safety and tolerability outcomes (primary) and efficacy outcomes (secondary). RESULTS: During 12 weeks of therapy with efalizumab or placebo, the incidence of clinical adverse events was 82.2% and 72.9%, respectively; the incidence of serious adverse events was 1.8% and 3.4%, respectively; and the incidence of nonserious adverse events leading to withdrawal was 1.8% and 1.7%, respectively. In the efalizumab group, there were no clinically significant changes in vital signs or laboratory parameters and no evidence of end-organ toxicities. A significantly higher proportion of patients receiving efalizumab than those receiving placebo achieved > or = 75% improvement in the Psoriasis Area and Severity Index (PASI) (P < 0.001), > or = 50% improvement in PASI (P < 0.001), and a static Physician's Global Assessment rating of Minimal or Clear (P < 0.001). The mean improvement in the Psoriasis Symptom Assessment was significantly greater in the efalizumab group (P < 0.001). CONCLUSIONS: Efalizumab treatment SC for 12 weeks was safe, well tolerated, and effective in patients with moderate to severe chronic plaque psoriasis.

Papp KA, Miller B, Gordon KB, Caro I, Kwon P, Compton PG, Leonardi CL, Anonymous00148. · Probity Medical Research, Waterloo, Ontario, Canada. · J Am Acad Dermatol. · Pubmed #16488338 No free full text.

Abstract: BACKGROUND: Efalizumab targets T cell-mediated steps important in psoriasis immunopathogenesis. OBJECTIVE: We sought to evaluate the efficacy and safety of efalizumab retreatment in patients with moderate to severe plaque psoriasis. METHODS: In this open-label, phase III study, 365 patients who received efalizumab therapy during an earlier clinical trial were retreated with 12 weeks of subcutaneous efalizumab (1 mg/kg/wk) 35 days or more after their last dose of efalizumab. RESULTS: After 12 weeks of efalizumab retreatment, 56.9% of patients achieved 50% or more improvement from baseline Psoriasis Area and Severity Index (PASI) and 25.3% achieved at least 75% reduction in PASI score. The mean percentage PASI improvement from baseline was 51.2%. Overall, 76.1% of patients surveyed were "very satisfied" or "satisfied" with the efficacy of efalizumab. The safety profile of efalizumab retreatment was similar to that observed in patients receiving efalizumab for the first time. LIMITATIONS: Not all patients received sufficient exposure to efalizumab during their previous efalizumab clinical trial to allow for determination of their initial response to efalizumab. Of 365 patients enrolled in the study, 282 received at least 12 weeks of prior efalizumab therapy; of these patients, 208 (73.8%) achieved a PASI-50 response from their previous therapy. CONCLUSION: These results suggest that retreatment with efalizumab therapy is an efficacious option for patients who have previously discontinued treatment.

Gordon KB, Bonish BK, Patel T, Leonardi CL, Nickoloff BJ. · Department of Internal Medicine, Division of Dermatology, Loyola University Medical Center, Maywood, IL 60153, USA. · Br J Dermatol. · Pubmed #16225604 No free full text.

Abstract: BACKGROUND: The pathophysiology of psoriasis is poorly understood, and the mechanism of action of biological agents interfering with tumour necrosis factor (TNF)-alpha that improve psoriatic plaques is completely unknown. OBJECTIVES: To begin to unravel the mechanism of action, cellular changes occurring in plaques following administration of adalimumab, a humanized monoclonal antibody against TNF-alpha, were investigated. METHODS: Thirteen different patients underwent sequential biopsies as part of a clinical trial. Each biopsy was immunostained and evaluated to calculate the relative density of epidermal Langerhans cells (LCs) before and after treatment (days 2, 7, 28, 84). To explore the basis for reduced epidermal LC densities in plaques, a SCID-Hu animal model was utilized. Acute psoriatic lesions were created within 2 weeks by injection of superantigen-activated CD4+ T cells into engrafted symptomless skin. RESULTS: Compared with symptomless skin, untreated plaques had a significantly reduced density of epidermal LCs. There was a rapid increase in density of epidermal LCs in plaques following treatment with adalimumab beginning as early as day 7. The paucity of epidermal LCs in plaques was contrasted to the prominent density of LCs in other skin disorders with chronic inflammation and alterations in keratinization, including lichen planus and inflamed seborrhoeic keratosis. Rapid creation of plaques using the SCID-Hu model was accompanied by loss of epidermal LCs, indicating that diminished LC density occurs at an early stage of lesion formation. CONCLUSIONS: These data shed light on a new immunopathological perspective highlighting a rapid loss of epidermal LCs in acute psoriatic lesions, with sustained decreased density of LCs in chronic plaques. Furthermore, an unexpected insight into the mechanism of action was uncovered for adalimumab, in which rapid restoration of epidermal LC density was observed.