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      Phosphodiesterase 4 Inhibition in the Treatment of Psoriasis, Psoriatic Arthritis and Other Chronic Inflammatory Diseases

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          Abstract

          Agents which increase intracellular cyclic adenosine monophosphate (cAMP) may have an antagonistic effect on pro-inflammatory molecule production so that inhibitors of the cAMP degrading phosphodiesterases have been identified as promising drugs in chronic inflammatory disorders. Although many such inhibitors have been developed, their introduction in the clinic has been hampered by their narrow therapeutic window with side effects such as nausea and emesis occurring at sub-therapeutic levels. The latest generation of inhibitors selective for phosphodiesterase 4 (PDE4), such as apremilast and roflumilast, seems to have an improved therapeutic index. While roflumilast has been approved for the treatment of exacerbated chronic obstructive pulmonary disease (COPD), apremilast shows promising activity in dermatological and rheumatological conditions. Studies in psoriasis and psoriatic arthritis have demonstrated clinical activity of apremilast. Efficacy in psoriasis is probably equivalent to methotrexate but less than that of monoclonal antibody inhibitors of tumour necrosis factor (TNFi). Similarly, in psoriatic arthritis efficacy is less than that of TNF inhibitors. PDE4 inhibitors hold the promise to broaden the portfolio of anti-inflammatory therapeutic approaches in a range of chronic inflammatory diseases which may include granulomatous skin diseases, some subtypes of chronic eczema and probably cutaneous lupus erythematosus. In this review, the authors highlight the mode of action of PDE4 inhibitors on skin and joint inflammatory responses and discuss their future role in clinical practice. Current developments in the field including the development of topical applications and the development of PDE4 inhibitors which specifically target the subform PDE4B will be discussed.

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          Most cited references 77

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          Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double-blind, randomized, placebo-controlled trial.

          Adalimumab, a fully human, anti-tumor necrosis factor monoclonal antibody, was evaluated for its safety and efficacy compared with placebo in the treatment of active psoriatic arthritis (PsA). Patients with moderately to severely active PsA and a history of inadequate response to nonsteroidal antiinflammatory drugs were randomized to receive 40 mg adalimumab or placebo subcutaneously every other week for 24 weeks. Study visits were at baseline, weeks 2 and 4, and every 4 weeks thereafter. The primary efficacy end points were the American College of Rheumatology 20% improvement (ACR20) response at week 12 and the change in the modified total Sharp score of structural damage at week 24. Secondary end points were measures of joint disease, disability, and quality of life in all patients, as well as the severity of skin disease in those patients with psoriasis involving at least 3% of body surface area. At week 12, 58% of the adalimumab-treated patients (87 of 151) achieved an ACR20 response, compared with 14% of the placebo-treated patients (23 of 162) (P < 0.001). At week 24, similar ACR20 response rates were maintained and the mean change in the modified total Sharp score was -0.2 in patients receiving adalimumab and 1.0 in those receiving placebo (P < 0.001). Among the 69 adalimumab-treated patients evaluated with the Psoriasis Area and Severity Index (PASI), 59% achieved a 75% PASI improvement response at 24 weeks, compared with 1% of the 69 placebo-treated patients evaluated (P < 0.001). Disability and quality of life measures were also significantly improved with adalimumab treatment compared with placebo. Adalimumab was generally safe and well-tolerated. Adalimumab significantly improved joint and skin manifestations, inhibited structural changes on radiographs, lessened disability due to joint damage, and improved quality of life in patients with moderately to severely active PsA.
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            The role of the transcription factor CREB in immune function.

            CREB is a transcription factor that regulates diverse cellular responses, including proliferation, survival, and differentiation. CREB is induced by a variety of growth factors and inflammatory signals and subsequently mediates the transcription of genes containing a cAMP-responsive element. Several immune-related genes possess this cAMP-responsive element, including IL-2, IL-6, IL-10, and TNF-α. In addition, phosphorylated CREB has been proposed to directly inhibit NF-κB activation by blocking the binding of CREB binding protein to the NF-κB complex, thereby limiting proinflammatory responses. CREB also induces an antiapoptotic survival signal in monocytes and macrophages. In T and B cells, CREB activation promotes proliferation and survival and differentially regulates Th1, Th2, and Th17 responses. Finally, CREB activation is required for the generation and maintenance of regulatory T cells. This review summarizes current advances involving CREB in immune function--a role that is continually being defined.
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              Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression.

              Etanercept has been shown to improve the articular and cutaneous manifestations of psoriatic arthritis (PsA). In this study, we further evaluated the safety, efficacy, and effect on radiographic progression of etanercept in patients with PsA. Patients with PsA (n = 205) were randomized to receive placebo or 25 mg etanercept subcutaneously twice weekly for 24 weeks. Patients continued to receive blind-labeled therapy in a maintenance phase until all had completed the 24-week phase, then could receive open-label etanercept in a 48-week extension. Efficacy and safety were evaluated at 4, 12, and 24 weeks and at 12-week intervals thereafter. Radiographs of the hands and wrists were assessed at baseline and 24 weeks, at entry to the open-label phase, and after 48 weeks in the study. Etanercept significantly reduced the signs and symptoms of PsA and psoriasis. At 12 weeks, 59% of etanercept patients met the American College of Rheumatology 20% improvement criteria for joint response, compared with 15% of placebo patients (P < 0.0001), and results were sustained at 24 and 48 weeks. At 24 weeks, 23% of etanercept patients eligible for psoriasis evaluation achieved at least 75% improvement in the Psoriasis Area and Severity Index, compared with 3% of placebo patients (P = 0.001). Radiographic disease progression was inhibited in the etanercept group at 12 months; the mean annualized rate of change in the modified total Sharp score was -0.03 unit, compared with +1.00 unit in the placebo group (P = 0.0001). Etanercept was well tolerated. Etanercept reduced joint symptoms, improved psoriatic lesions, inhibited radiographic progression, and was well tolerated in patients with PsA.
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                Author and article information

                Contributors
                p.helliwell@leeds.ac.uk
                Journal
                Dermatol Ther (Heidelb)
                Dermatol Ther (Heidelb)
                Dermatology and Therapy
                Springer Healthcare (Cheshire )
                2193-8210
                2190-9172
                27 April 2013
                27 April 2013
                June 2013
                : 3
                : 1
                : 1-15
                Affiliations
                [ ]NIHR Leeds Musculoskeletal Biomedical Research Unit, Section of Musculoskeletal Disease, Chapel Allerton Hospital, Chapel Town Road, Leeds, LS7 4SA UK
                [ ]Centre for Skin Sciences, School of Life Sciences, University of Bradford, Bradford, UK
                [ ]Department of Dermatology, Bradford NHS Trust, Bradford, UK
                [ ]Department of Rheumatology, Bradford NHS Trust, Bradford , UK
                Article
                23
                10.1007/s13555-013-0023-0
                3680635
                23888251
                © The Author(s) 2013
                Categories
                Review
                Custom metadata
                © Springer Healthcare 2013

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