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      Drug Design, Development and Therapy (submit here)

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      Profile of certolizumab and its potential in the treatment of psoriatic arthritis


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          Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy associated with psoriasis (PsO). PsA could be considered an enthesal disease because of the link between mechanical stress (entheses) and immunologically active tissue (synovium). Evidence of efficacy of anti-tumor necrosis factor alpha (TNF-α) is supported by reduction of histological vascularity and immune cell infiltrates in synovial tissue after treatment. Certolizumab pegol (CZP) is a polyethylene glycolylated (PEGylated) Fab’ fragment of a humanized monoclonal antibody that binds and neutralizes human TNF-α. The PEG moiety of the Fab fragment, markedly increases the half-life of CZP and confers to the drug a unique structure that differs from the other anti-TNF-α agents tested for the treatment of Crohn’s disease, rheumatoid arthritis, ankylosing spondylitis, axial spondyloarthritis, nonradiographic spondyloarthritis, PsO, and PsA. In contrast to other anti-TNF-α agents, CZP did not mediate increased levels of apoptosis, suggesting that these mechanisms are not essential for the anti-TNF-α efficacy in Crohn’s disease. As CZP, infliximab, and adalimumab, but not etanercept, almost completely inhibited lipopolysaccharide-induced interleukin-1 beta release from monocytes, this cytokine-production inhibition may be relevant for drug efficacy. Due to these characteristics, it has been demonstrated in clinical studies that CZP effectively improves signs and symptoms of arthritis and physical function and skin manifestations of PsO, with a safety profile similar to rheumatoid arthritis. This drug can be considered as a valid treatment in patients affected by PsA. The efficacy and tolerability profiles suggest CZP as a suitable antipsoriatic drug in the treatment of PsA.

          Most cited references51

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          Pegylation: a novel process for modifying pharmacokinetics.

          The use of liposomal carriers and the modification of therapeutic molecules through the attachment of poly(ethylene glycol) [PEG] moieties ('pegylation') are the most common approaches for enhancing the delivery of parenteral agents. Although 'classical' liposomes (i.e. phospholipid bilayer vehicles) have been effective in decreasing the clearance of encapsulated agents and in passively targeting specific tissues, they are associated with considerable limitations. Pegylation may be an effective method of delivering therapeutic proteins and modifying their pharmacokinetic properties, in turn modifying pharmacodynamics, via a mechanism dependent on altered binding properties of the native protein. Pegylation reduces renal clearance and, for some products, results in a more sustained absorption after subcutaneous administration as well as restricted distribution. These pharmacokinetic changes may result in more constant and sustained plasma concentrations, which can lead to increases in clinical effectiveness when the desired effects are concentration-dependent. Maintaining drug concentrations at or near a target concentration for an extended period of time is often clinically advantageous, and is particularly useful in antiviral therapy, since constant antiviral pressure should prevent replication and may thereby suppress the emergence of resistant variants. Additionally, PEG modification may decrease adverse effects caused by the large variations in peak-to-trough plasma drug concentrations associated with frequent administration and by the immunogenicity of unmodified proteins. Pegylated proteins may have reduced immunogenicity because PEG-induced steric hindrance can prevent immune recognition. Two PEG-modified proteins are currently approved by the US Food and Drug Administration; several others, including cytokines such as interferon-alpha (IFNalpha), growth factors and free radical scavengers, are under development. Careful assessment of various pegylated IFNalpha products suggests that pegylated molecules can be differentiated on the basis of their pharmacokinetic properties and related changes in pharmacodynamics. Because the size, geometry and attachment site of the PEG moiety play a crucial role in determining these properties, therapeutically optimised agents must be designed on a protein-by-protein basis.
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            A prospective, clinical and radiological study of early psoriatic arthritis: an early synovitis clinic experience.

            To determine the clinical presentation and clinical and radiological outcome of early psoriatic arthritis (PsA) at 1 and 2 yr. Patients with PsA were assessed at the St. Vincent's University Hospital Early Synovitis Clinic. Standardized clinical and laboratory assessment was performed at presentation and 1- and 2-yr follow-up. Radiographs of the hands and feet were evaluated in chronological order by two trained observers using the Sharp method modified to include the distal interphalangeal (DIP) joints. A total of 129 (12.7%) of 1018 patients were diagnosed with PsA [mean age at onset of arthritis was 40.4 yr (range 11-76); mean duration of disease was 9.9 months (range 0.3-48); 52 oligoarticular, 77 polyarticular]. Means and standard deviations of indices of disease activity at presentation were: 10-cm visual analogue scale = 4.8 +/- 2.7, HAQ score = 0.71 +/- 0.64, ACR functional class III/IV = 41 (35%), Ritchie Articular Index = 5.6 +/- 6, swollen joint count = 6.9 +/- 8, erythrocyte sedimentation rate = 24 +/- 26.4 mm/h, C-reactive protein = 27.6 +/- 58.5 mg/l. At presentation, 49 (38%) patients had peripheral enthesopathy, 13 patients (10%) had inflammatory spine pain and 50 (39%) patients had DIP involvement. A total of 119 had psoriasis at the time of presentation [plaque psoriasis in 112 (94%), mean age of psoriasis onset was 29.8 +/- 16.2 yr, nail dystrophy present in 78 patients (67%)]. At 1 yr of follow-up, 119 (92%) patients were reassessed and 70 (59%) were taking a disease-modifying anti-rheumatic drug (DMARD). At 2 yr, 97 (75%) patients were reassessed and 54 (56%) were taking a DMARD. Despite considerable improvement in inflammation and function scores, only 31 (26%) patients were in remission at 1 yr with 20 (21%) in remission at 2 yr. There was a low rate of DMARD-free remission [14 (12%) at 1 yr and 11 (11%) at 2 yr]. Radiographs of hands and feet were obtained for 117 (91%) patients at presentation and 86 (67%) patients at a median follow-up of 24 months (range 11-56); 47% of patients had joint erosions in hands or feet at follow-up with a mean Sharp erosion score of 3 (0) +/- 5.2 (range 0-25) and a mean Sharp narrowing score of 3.2 (0) +/- 7.5 (range 0-48). This study confirms that PsA is a chronic, progressive disease in the majority of patients. Despite clinical improvement with current DMARD treatment, PsA results in radiological damage in up to 47% of patients at a median interval of 2 yr.
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              Psoriasis--epidemiology and clinical spectrum.

              Despite psoriasis being a common skin disease, there are still a number of unanswered questions. One of these is the prevalence of the disease, as there is a lack of specific data, with the majority of studies reporting estimates only. Population based studies are rare and longitudinal observations on changing prevalence rates are lacking. This contrasts with other T-cell mediated autoimmune diseases where the number of those affected is rising. Epidemiological studies revealed that a distinct group of diseases is quite frequently associated with psoriasis, e.g. arthritis, colitis, diabetes and hypertension. In contrast, atopic dermatitis and allergies are less frequently seen compared to normal rates of occurrence. As the psoriatic immune response pattern relates to activated Th-1 cells, psoriasis and atopic dermatitis appear to be mutually exclusive due to the Th-1/Th-2 dichotomy.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Dove Medical Press
                15 April 2013
                : 7
                : 339-348
                [1 ]Unit of Rheumatology, Allergology, and Clinical Immunology, University of Rome Tor Vergata, Rome, Italy
                [2 ]Unit of Dermatology, University of Rome Tor Vergata, Rome, Italy
                [3 ]Laboratory for Investigative Dermatology, Rockefeller University, New York, NY, USA
                Author notes
                Correspondence: Maria Sole Chimenti, Unit of Rheumatology, Department of Internal Medicine, University of Rome Tor Vergata, 1 Via Montpellier, Rome 00163, Italy, Tel +39 06 2090 0587, Fax +39 06 2090 0358, Email maria.sole.chimenti@ 123456uniroma2.it
                © 2013 Chimenti et al, publisher and licensee Dove Medical Press Ltd.

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.


                Pharmacology & Pharmaceutical medicine
                psoriatic arthritis,certolizumab pegol,biological therapies,anti-tnf


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