Rheumatoid Arthritis: Italy

Valesini G, Montecucco C, Cutolo M. · Italian Society for Rheumatology. Cattedra di Reumatologia, Università di Roma La Sapienza, Italy. · Clin Exp Rheumatol. · Pubmed #16956432 No free full text.

Abstract: The present report is devoted to drawing up and disseminating specific recommendations for the use of anti-TNF-alpha therapies in patients with rheumatoid arthritis (RA) in Italy. The document reports and discusses the published literature concerning the criteria for inclusion, assessment of response and for withdrawal of treatment with TNF blocking agents in RA. Several specific points concerning more sensitive warnings are discussed: tuberculosis, hepatitis, lymphoma, and cardiovascular risk and induction of autoimmunity. The recommendations are summarized in an 8-point table approved by the executive committee of the Italian Society for Rheumatology.

Schiavon F, Favero M, Carraro V, Riato L. · U.O.C. di Reumatologia, Azienda Ospedale-Università, 35128 Padova, Italia. · Reumatismo. · Pubmed #18432319 links to  free full text

Abstract: Septic arthritis (SA) is a clinical emergency with considerable morbidity and mortality that can lead to rapid joint destruction and irreversible loss of function. The reported incidence varies from 2-5 cases per 100.000 individuals per year in the general populations to 70 cases per 100.000 individuals annually among patients with rheumatoid arthritis (RA). Predisposing factors are immunosuppressive and corticosteroids therapy and RA "itself". The expected decrease in incidence of SA was not seen over the last 20 years period but we can, on the contrary, expect an increase in the frequency of its appearance because of the population ageing, the increasingly prosthetic joint replacement, the ability of the bacteria to evade clearance by the host immune response and the rapidly growing number of patients with RA, ankylosing spondylitis and psoriatic arthritis treated with tumour necrosis factor alpha (TNF alpha) antagonists. Up to now there have been conflicting reports regarding joint infections in patients under anti-TNF therapy but according to data from Deutsch as well as the British register there might be an increase in the incidence of joint infections in anti-TNF treated patients. Microscopic analysis and culture of synovial fluid are fundamental diagnostic tools in the evaluation of possible joint sepsis. Sonographic guidance of arthrocentesis led to successful aspiration of difficult-to-access joints as shoulder and hip. There is controversy over which mode of drainage of septic synovial fluid should be employed but needle aspiration appear to be preferable to surgical treatment as an initial mode of treatment of SA. Rheumatologists should have a central role in the diagnosis and management of SA.

Cutolo M. · Department of Internal Medicine, University of Genova, Genova, Italy. · Clin Exp Rheumatol. · Pubmed #15083879 No free full text.

This publication has no abstract.

Volpi N, Schiller J, Stern R, Soltés L. · Department of Biologia Animale, University of Modena & Reggio Emilia, Via Campi 213/d, I-41100 Modena, Italy. · Curr Med Chem. · Pubmed #19442142 No free full text.

Abstract: Hyaluronan (hyaluronic acid, HA) is a linear naturally occurring polysaccharide formed from repeating disaccharide units of N-acetyl-D-glucosamine and D-glucuronate. Despite its relatively simple structure, HA is an extraordinarily versatile glycosaminoglycan currently receiving attention across a wide front of research areas. It has a very high molar mass, usually in the order of millions of Daltons, and possesses interesting visco-elastic properties based on its polymeric and polyelectrolyte characteristics. HA is omnipresent in the human body and in other vertebrates, occurring in almost all biological fluids and tissues, although the highest amounts of HA are found in the extracellular matrix of soft connective tissues. HA is involved in several key processes, including cell signaling, wound repair and regeneration, morphogenesis, matrix organization and pathobiology. Clinically, it is used as a diagnostic marker for many disease states including cancer, rheumatoid arthritis, liver pathologies, and as an early marker for impending rejection following organ transplantation. It is also used for supplementation of impaired synovial fluid in arthritic patients, following cataract surgery, as a filler in cosmetic and soft tissue surgery, as a device in several surgical procedures, particularly as an anti-adhesive following abdominal procedures, and also in tissue engineering. This review will provide an overview of the structure and physiological role of HA, as well as of its biomedical and industrial applications. Recent advances in biotechnological approaches for the preparation of HA-based materials, and as a component of tissue scaffolding for artificial organs will also be presented.

Sales C, Oliviero F, Spinella P. · Servizio di Dietetica e Nutrizione Clinica, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Padova, Padova, Italia. · Reumatismo. · Pubmed #19370182 links to  free full text

Abstract: The Mediterranean diet is based on a pattern of eating closely tied to the Mediterranean region, which includes Greece and southern Italy. Essentially, the traditional diet emphasizes foods from plant sources, limited meat consumption, small amounts of wine and olive oil as the main fat source. The beneficial effects of the Mediterranean diet has been proven not only to cardiovascular diseases but also for diabetes, obesity, arthritis and cancer. Its anti-inflammatory and protective properties are linked to the large presence of omega-3 polyunsaturated fatty acids, vitamins, but especially to the constituents of extra virgin olive oil: oleic acid, phenolic compounds olecanthal, a new recently discovered molecule, with natural anti-inflammatory properties. It has been shown that the Mediterranean diet can reduce disease activity, pain and stiffness in patients with inflammatory arthritis and may thus constitute a valuable support for patients suffering from these diseases.

Fietta P, Delsante G, Quaini F. · Dipartimento Medico Polispecialistico, S.D. di Medicina Interna e Reumatologia, Azienda Ospedaliero-Universitaria di Parma, Italy. · Clin Exp Rheumatol. · Pubmed #19327244 No free full text.

Abstract: Autoimmune connective tissue diseases (ACTDs) constitute a heterogeneous group of chronic immune-mediated inflammatory disorders, primarily affecting connective tissues and usually characterized by multisystem involvement with variable and frequently overlapping clinical manifestations. Abnormal immune regulation patterns and persistent inflammation are ACTD hallmarks. In such a context, autoimmunity/inflammation-associated cellular and molecular networks drive a complex of reactions that may involve hemopoietic tissue and peripheral blood cells. Hematologic abnormalities affecting one or more cellular lineages are frequent manifestations of ACTDs, and may represent an important prognostic factor, reflecting the rate of activation of autoimmune/inflammatory processes. Moreover, an increased frequency of hematologic malignancies, mainly lymphoproliferative disorders, has been observed in ACTDs, such as Sjögren's syndrome, systemic lupus erythematosus, rheumatoid arthritis, and polymyositis/dermatomyositis. A proliferative drive likely constitutes the link between chronic immune activation/dysregulation and malignant transformation, creating an increased risk for genetic aberrations that may lead to uncontrolled clonal proliferation. Revealing the nature of lymphomagenesis in relation to autoimmunity/inflammation will allow the identification of subjects at risk in order to select the appropriate diagnostic and therapeutic options. In this paper, the main hematologic manifestations of adulthood ACTDs are reviewed and discussed.

Giannitti C, Bellisai F, Ferri C, Galeazzi M. · University of Siena, Department of Clinical Medicine and Immunological Science, Rheumatology Section, Policlinico Le Scotte, Siena, Italy. · Expert Opin Pharmacother. · Pubmed #19284361 No free full text.

Abstract: BACKGROUND: The poor prognosis of rheumatoid arthritis (RA) can be aggravated by the concomitant presence of chronic hepatitis C virus (HCV) infection and there are no guidelines for the treatment of patients affected by both conditions. OBJECTIVE: To propose new therapeutic strategies for patient affected by RA and concomitant HCV chronic infection. METHODS: Review of the literature on the usage of cyclosporine-A (CsA) and anti-tumour-necrosis-factor (TNF)-alpha agents for the treatment of patients affected by RA and HCV. RESULTS/CONCLUSION: CsA exerts an inhibitory effect on HCV replication and it is safe in patients affected by RA and HCV. Anti-TNF-alpha agents are safe and efficacious in patient with RA and HCV. Anti-TNF-alpha and CsA can be safely given in combination in RA patients with HCV infection.

Santilli F, Vazzana N, Bucciarelli LG, Davì G. · Center of Excellence on Aging, "G. D'Annunzio" University Foundation, Chieti, Italy. · Curr Med Chem. · Pubmed #19275604 No free full text.

Abstract: The ligand - receptor for advanced glycation end-products (RAGE) axis has emerged as a novel pathway involved in a wide spectrum of diseases, including diabetes mellitus, atherothrombosis, chronic renal failure, rheumatoid arthritis, neurodegeneration, cancer and aging. Circulating soluble forms of RAGE (sRAGE), arising from receptor ectodomain shedding and splice variant [endogenous secretory (es) RAGE] secretion, may counteract RAGE-mediated pathogenesis, by acting as a decoy. Several studies suggest that decreased levels of sRAGE and/or esRAGE may be useful as a biomarker of ligand-RAGE pathway hyperactivity and inadequate endogenous protective response, thus providing a powerful complement to cardiovascular risk stratification and an interesting target of therapeutic interventions. This review will focus on the pathophysiological determinants of soluble forms of RAGE in different clinical settings, with particular reference to the mechanisms involved in their generation and clearance, the association with cardiovascular risk factors, the interplay with low-grade inflammation, oxidative stress and endothelial dysfunction, and the possible pharmacological modulation of their plasma levels.

Monteleone G, Pallone F, Macdonald TT. · Department of Internal Medicine, University of Rome Tor Vergata, Via Montpellier, 1, 00133, Rome, Italy. · Cytokine Growth Factor Rev. · Pubmed #19261537 No free full text.

Abstract: Interleukin-21 (IL-21) is produced mostly by activated CD4+ T cells and controls the differentiation and functional activity of effector T helper cells, counteracts the suppressive effects of regulatory T cells, and stimulates non-immune cells to make inflammatory mediators. IL-21-driven tissue damage has been demonstrated in a number of organs, such as the gut, pancreas, and brain. Therefore new treatment modalities to neutralise IL-21 in vivo would be a valuable addition to the therapeutic armamentarium to combat immune-mediated inflammation. Here we describe the emerging role of IL-21 in the initiation and progress of the tissue-damaging inflammatory response in immune-mediated pathologies.

Laganà B, Vinciguerra M, D'Amelio R. · Azienda Ospedaliera S. Andrea, University of Rome Sapienza II, Department of Immunology, Allergology and Rheumatology, Rome, Italy. · Clin Drug Investig. · Pubmed #19243211 No free full text.

Abstract: Rheumatoid arthritis (RA), characterized by progressive joint destruction, deformity, disability and impaired quality of life (QOL), is a prevalent autoimmune disease affecting 1% of adults in the US. The goal of therapy in patients with RA is to arrest the disease and to achieve remission by preventing or controlling joint damage, preventing loss of function and providing pain relief, thereby improving QOL. Non-biological disease-modifying antirheumatic drugs (DMARDs) have been the mainstay of early intervention in RA, of which methotrexate has been used most frequently. However, in the long term, patients treated with non-biological DMARDs (including methotrexate) may experience joint deterioration and subclinical inflammation even after clinical remission, emphasizing the need for alternative therapies. Several biological therapies, such as anti-tumour necrosis factor (TNF)-alpha agents, have been developed in the last decade and may be used either as monotherapy or in combination with non-biological DMARDs. Although anti-TNFalpha therapy is generally associated with an improvement in symptoms of RA, some patients may experience inadequate response to or may not tolerate these agents. The new biological agent abatacept, a recombinant protein consisting of the extracellular region of the human cytotoxic T-lymphocyte-associated antigen (CTLA)-4 receptor fused to the constant fragment (Fc) region of IgG1, binds to the CD80/CD86 molecules on antigen-presenting cells and modulates T-cell activation. Clinical trials have shown that abatacept is effective in reducing disease activity, structural joint damage and improving QOL in patients with RA who had inadequate response to prior methotrexate or anti-TNFalpha therapy. Pooled analysis of these trials showed that abatacept was also generally well tolerated in these patients. Thus, abatacept therapy may be an option for the treatment of RA in patients who have had an inadequate response to prior DMARD therapy.

Arioli G, Maddali Bongi S, Pappone N. · Dipartimento di Riabilitazione e Reumatologia, Azienda Ospedaliera C. Poma, 46100 Mantova, Italia. · Reumatismo. · Pubmed #19132147 links to  free full text

Abstract: The rehabilitative approach for the patient with rheumatoid arthritis should be early, global and complementary to an early pharmacological therapy, in the context of a multidisciplinary approach, that should include physicians with different specialties and other health professionals. Evaluation scales assessing disability and quality of life are necessary for the rehabilitative approach. These can be classified in 2 groups: specific tools and generic tools, each evaluating different components of the health status. After the evaluation and the definition of the aims of the rehabilitation, a rehabilitative project, potentially including physical therapies, therapeutic exercises, occupational therapy and orthosis should be defined.

Gerosa M, De Angelis V, Riboldi P, Meroni PL. · San Luca Hospital, Allergy, Clinical Immunology & Rheumatology Unit, Via G Spagnoletto 3, 20149 Milan, Italy. · Womens Health (Lond Engl). · Pubmed #19072521 No free full text.

Abstract: Rheumatoid arthritis (RA) is two- to three-fold more frequent in women than in men and a strong association with sex hormones has been demonstrated. There is strong evidence that autoimmunity is under genetic control, and genes in sexual chromosomes can play a role in supporting the female prevalence. On the other hand, it is widely accepted that sex hormones--estrogens in particular--may regulate the immune response by favoring the survival of forbidden autoreactive clones and ultimately the prevalence of autoimmunity in women. Accordingly, estrogens have been suggested to be associated with the development of RA. Pregnancy in RA women is a common situation and most pregnant patients experience a remission. This has been closely related to a switch from Th1 to Th2 immune responses and to a decreased production of proinflammatory cytokines, at least in part supported by the changes of the hormonal profile in pregnancy. Pregnancy planning is required in RA in order to avoid unwanted complications. In particular, the need to control the disease requires safe use of antirheumatic drugs both during the pregnancy itself and in the breastfeeding period. Hormonal treatment for contraception is contraindicated in the case of positivity for antiphospholipid antibodies owing to the increased thrombophilic risk. Similarly, replacement hormonal treatment in postmenopausal women with RA to control osteoporosis is no longer recommended as a result of its ability to increase the cardiovascular risk closely associated with RA itself.

Caporali R, Caprioli M, Bobbio-Pallavicini F, Montecucco C. · Rheumatology, University of Pavia, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy. · Autoimmun Rev. · Pubmed #19014871 No free full text.

Abstract: Patients with rheumatoid arthritis (RA) has an increased infections risk and morbidity and mortality related to infections. This increased risk may occur due to the disease itself with intrinsic cellular immunity alterations or as a results of drugs used to control the disease. The potential risk of infections related to conventional disease modifying anti-rheumatic drugs (DMARDs) is not completely clarified. Methotrexate (MTX) may increase the infectious risk, but its positive effect on disease activity results in a reduction of further risk factors for infections. Data about the increased risk of pneumonia or reactivation of silent infection remain controversial. Leflunomide (LEF) seems safe in controlled trial even if it has been associated with the onset of infections requiring hospitalization, such as pneumonia. Data about other DMARDs are scanty and the main cause of interruption of therapy is related to toxicity different from infection. Beside the general positive profile of DMARDs as for infectious risk, a careful use and tight control of the patients is recommended.

Vitali C. · Department of Internal Medicine and Section of Rheumatology, 'Villamarina' Hospital, Piombino, Italy. · Rheum Dis Clin North Am. · Pubmed #18984415 No free full text.

Abstract: Sjögren's syndrome (SS) is a systemic autoimmune disease that is characterized by an aggressive autoimmune response to epithelia, with consequent reduction of their secretions accompanied by sicca complaints. Systemic features may also be present in a subset of patients and may require more aggressive therapies. Improvements in knowledge concerning disease pathophysiology, combined with the availability of specifically targeted therapies able to modulate or block some of the most important pathologic mechanisms of the disease, may open totally new perspectives in the therapeutic approach to SS. The absence of reliable and validated outcome measures for SS is a major obstacle in performing clinical trials of new therapies in SS but studies devoted to defining outcome measurement instruments for this disorder have been performed or are in an advanced phases of completion.

Gatto B. · University of Padova, Department of Pharmaceutical Sciences, Padova, Italy. · Curr Opin Investig Drugs. · Pubmed #18951301 No free full text.

Abstract: Atacicept (TACI:Fc5) is a homodimeric fusion protein obtained through recombinant DNA technology being developed by Merck Serono SA, under license from ZymoGenetics Inc, for the potential treatment of B-cell diseases. Atacicept is undergoing phase II/III clinical trials for systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, multiple sclerosis, as well as for several B-cell malignancies.

Ruperto N, Martini A. · IRCCS Istituto G. Gaslini, Pediatria II, Reumatologia, Genoa, Italy. · World J Pediatr. · Pubmed #18822926 No free full text.

Abstract: BACKGROUND: Pediatric rheumatic diseases (PRDs) are rare conditions associated with significant sequelae affecting the quality of life and long-term outcome. The research aimed at studying new therapeutic approaches is difficult because of logistic, methodological and ethical problems. DATA SOURCES: To address these problems, two international networks, the Pediatric Rheumatology Collaborative Study Group (PRCSG) and the Pediatric Rheumatology International Trials Organization (PRINTO) were established. The two networks share the goal to promote, facilitate and conduct high quality research for PRDs. RESULTS: The PRINTO and PRCSG networks have standardized the evaluation of response to therapy in juvenile idiopathic arthritis (JIA), juvenile systemic lupus erythematosus, and juvenile dermatomyositis, drafted clinical remission criteria in JIA, and provided cross-cultural adapted and validated quality of life instruments including the Childhood Health Assessment Questionnaire and the Child Health Questionnaire into 32 different languages. In this paper we reviewed how the networks of the PRINTO and PRCSG have created the basic premises for the best future assessment of PRDs. CONCLUSIONS: The PRINTO and PRCSG networks can be regarded as a model for international cooperation or collaboration in other pediatric subspecialties.

Sitia S, Atzeni F, Sarzi-Puttini P, Di Bello V, Tomasoni L, Delfino L, Antonini-Canterin F, Di Salvo G, De Gennaro Colonna V, La Carrubba S, Carerj S, Turiel M. · IRCCS Orthopedic Galeazzi Institute, University of Milan, Department of Health Technologies, Cardiology Unit, Milan, Italy. · Autoimmun Rev. · Pubmed #18817899 No free full text.

Abstract: Autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary antiphospholipid syndrome (APS), systemic sclerosis and systemic vasculitis, affect a large number of people in whom one of the leading causes of morbidity and mortality is cardiovascular disease. Cardiovascular disease is associated with the development of accelerated atherosclerosis. It seems to occur at a younger age than in the general population, is often asymptomatic and, in addition to traditional risk factors, also involves specific risk factors as chronic inflammation, the duration and activity of the autoimmune disease, and immunosuppressive therapy. The early phases of cardiovascular involvement in patients with autoimmune diseases may be clinically silent, with only a microcirculation disorder present. There are various means of detecting morphological cardiac damage: coronary angiography remains the gold standard for diagnosing coronary stenosis, but new, non invasive and more reliable methods have been introduced into clinical practice in order to detect subclinical microcirculation abnormalities.

Valesini G, Di Franco M, Spinelli FR, Scrivo R. · Dipartimento di Clinica e Terapia Medica, Reumatologia, Sapienza, Università di Roma, Policlinico Umberto I, 00161, Rome, Italy. · Rheumatol Int. · Pubmed #18807254 No free full text.

Abstract: The concept of remission in rheumatology is complicated by the lack of a single gold standard measurement, spontaneous remissions and the usage of several sets of remission criteria. Feasibility is reduced by traditional clinical practice, which does not include remission criteria monitoring. The "window of opportunity" to prevent joint damage with DMARD therapy lasts only a few months. The perspective of the physician and patient differ, as the former gives importance to signs of disease activity, whereas the latter to disability and quality of life. All patients with rheumatoid arthritis are candidates for combination DMARD-based therapy, which should be instituted without delay. Remission is important to prevent joint destruction, preserve adequate quality of life and prevent disability. The introduction of biological agents has made this objective feasible, but the failure rate is still high (about 50%), on account of lack of response, contraindications and intolerance.

Di Munno O, Delle Sedie A. · U.O. Reumatologia, Dipartimento di Medicina Interna, Università di Pisa, 56126 Pisa, Italy. · J Endocrinol Invest. · Pubmed #18791351 No free full text.

Abstract: Rheumatoid arthritis (RA) is characterized by an extensive dysregulation in skeletal homeostasis recognized as 1) focal articular bone erosions, 2) iuxta-articular osteopenia, 3) systemic osteoporosis (OP) and fractures, as is well documented in both cross-sectional and prospective studies. The disease activity, as a consequence of new insights into the complex interaction between bone cells and a variety of cells of the immune system, has emerged as the main responsible for both focal and systemic bone loss. Given this background, the therapeutic approach to RA has become more aggressive, and a more widespread use of low-dose glucocorticoids (GC), recently categorized as disease modifying antirheumatic drugs (DMARD) because of their additional joint sparing effect on the long-term, has also been recommended from the early stages. Addressing the effects of GC on systemic bone loss in RA, GC are considered, in addition to inflammation and inactivity, the major risk factors for OP and fractures. As a consequence, among the most recent recommendations (i.e. dosing, timing, and tapering strategies) for patients receiving GC for more than 3 months, prevention and treatment of GC-induced OP (i.e. calcium, vitamin D, and bisphosphonates) are included. However, innovative GC, characterized by a more favorable risk/benefit profile such as selective GC receptor agonists (SEGRA), are currently in the pipeline. This article reviews the major points of evidence so far available, regarding the effects of GC on focal and systemic bone loss.

Toffoli G, De Mattia E. · Experimental and Clinical Pharmacology Unit, CRO National Cancer Institute via Franco Gallini, 2, 33081 Aviano (PN), Italy. · Pharmacogenomics. · Pubmed #18781847 No free full text.

Abstract: The 5,10-methylenetetrahydrofolate reductase (MTHFR) is a key enzyme for intracellular folate homeostasis and metabolism. Two common MTHFR polymorphisms, C677T and A1298C, which lead to an altered amino acid sequence, have been associated with a decreased enzyme activity and susceptibility to cancer suggesting that these genetic variants may modulate the risk of several malignancies. C667T, and to a lesser extent A1298C polymorphisms, are also reported to influence the cytotoxic effect of fluoropyrimidines and antifolates providing support for their pharmacogenetic role in predicting the efficacy and the toxicity in cancer and rheumatoid arthritis patients. A combined polymorphisms and haplotype analysis may result in a more effective approach than a single polymorphism one. Moreover gene-nutrient/environmental and gene-racial/ethnic interactions have been shown to affect the impact of these MTHFR genetic variants. Further well-designed studies are needed to clarify the role of MTHFR polymorphisms to derive dose adjustment recommendations on the basis of the patient's genotype.

Veronese FM, Mero A. · Department of Pharmaceutical Sciences, Padua University, Padua, Italy. · BioDrugs. · Pubmed #18778113 No free full text.

Abstract: The term PEGylation describes the modification of biological molecules by covalent conjugation with polyethylene glycol (PEG), a non-toxic, non-immunogenic polymer, and is used as a strategy to overcome disadvantages associated with some biopharmaceuticals. PEGylation changes the physical and chemical properties of the biomedical molecule, such as its conformation, electrostatic binding, and hydrophobicity, and results in an improvement in the pharmacokinetic behavior of the drug. In general, PEGylation improves drug solubility and decreases immunogenicity. PEGylation also increases drug stability and the retention time of the conjugates in blood, and reduces proteolysis and renal excretion, thereby allowing a reduced dosing frequency. In order to benefit from these favorable pharmacokinetic consequences, a variety of therapeutic proteins, peptides, and antibody fragments, as well as small molecule drugs, have been PEGylated.This paper reviews the chemical procedures and the conditions that have been used thus far to achieve PEGylation of biomedical molecules. It also discusses the importance of structure and size of PEGs, as well as the behavior of linear and branched PEGs. A number of properties of the PEG polymer--e.g. mass, number of linking chains, the molecular site of PEG attachment--have been shown to affect the biological activity and bioavailability of the PEGylated product. Releasable PEGs have been designed to slowly release the native protein from the conjugates into the blood, aiming at avoiding any loss of efficacy that may occur with stable covalent PEGylation.Since the first PEGylated drug was developed in the 1970s, PEGylation of therapeutic proteins has significantly improved the treatment of several chronic diseases, including hepatitis C, leukemia, severe combined immunodeficiency disease, rheumatoid arthritis, and Crohn disease. The most important PEGylated drugs, including pegademase bovine, pegaspargase, pegfilgrastim, interferons, pegvisomant, pegaptanib, certolizumab pegol, and some of the PEGylated products presently in an advanced stage of development, such as PEG-uricase and PEGylated hemoglobin, are reviewed. The adaptations and applications of PEGylation will undoubtedly prove useful for the treatment of many previously difficult-to-treat conditions.

Ottolenghi L, Bertele' V, Garattini S. · Laboratory of Regulatory Policies, Mario Negri Institute for Pharmacological Research, Via Giuseppe La Masa 19, 20156 Milan, Italy. · Eur J Clin Pharmacol. · Pubmed #18762934 No free full text.

Abstract: PURPOSE: This paper assesses the design of clinical studies used in the process of regulatory approval, focusing on how add-on studies affect regulatory decisions. METHODS: The sample case taken is that of the new agents for rheumatoid arthritis (RA) authorised by the European Medicine Agency (EMEA). The European Public Assessment Reports (EPARs) accompanying the marketing authorisations were the source of information on the studies presented in the registration dossiers. RESULTS: The recently approved anti-RA agents are all indicated in combination with methotrexate (MTX) for treating adults with active RA who have responded inadequately to disease-modifier drugs (DMARDs). The add-on design was frequently used in registration studies. For infliximab, etanercept, adalimumab and rituximab, add-on trials contributed, together with parallel-group trials, to gaining the approval as combination therapy. Anakinra and abatacept were authorised on the basis of add-on trial results only. CONCLUSIONS: Add-on trials do not allow assessment of the intrinsic efficacy and safety of new agents and their value as alternatives to available treatments. The indications granted for the new anti-RA agents do not specify whether newer drugs can replace standard treatments in nonresponders, can do better in the overall patient population or can be used as first-line treatment.

Fiocco U, Sfriso P, Oliviero F, Pagnin E, Scagliori E, Campana C, Dainese S, Cozzi L, Punzi L. · Rheumatology Unit, University of Padova, Via Giustiniani 2-35128 Padova, Italy. · Autoimmun Rev. · Pubmed #18718877 No free full text.

Abstract: Associations between rheumatoid arthritis (RA) susceptibility and polymorphism in multiple immunoregulatory genes suggest a role of altered T cell function in the disease. The growing relevance of the oxidative stress in RA synovitis, which results in a number of T cell signalling abnormalities, is reinforced by the demonstration of a direct NO inducing activity through the shared epitope of the HLA class II molecules HLA-DRbeta1, with secondary lymphocytes oxidative damage. Direct T cell/macrophage contact-dependent activation, one of the driving mechanisms of synovitis, is mediated by co-stimulatory molecules as well as cell membrane cytokines and may also result in an impaired suppressive function of T regulatory cells (Treg) in RA joints. The fusion of CTLA4 extracellular binding domain to the Fcgamma1 allows to obtain a soluble CTLA4 receptor, the dimeric recombinant human fusion protein abatacept (CTLA4-Ig). The improved knowledge of the CTLA4-B7 co-stimulation regulatory mechanisms by signals delivered into DCs and Tregs provides multiple potential targets for the abatacept treatment. CTLA4-Ig shows the capacity, either ex vivo or in vivo, to interrupt at multiple steps the ongoing inflammatory and destructive process, and to concur in restoring the immunoregulatory balance in RA.

Manfredi M, Benucci M. · U.O.S. Laboratorio Immunologia Allergologia, Nuovo Ospedale S.Giovanni di Dio, ASL 10 Firenze. · Recenti Prog Med. · Pubmed #18710059 No free full text.

Abstract: Cytokines such as TNF-alpha and IL-1beta play key roles in driving the inflammation and synovial cell proliferation that characterize rheumatoid arthritis (RA) joint destruction. It is, therefore, not surprising that therapies for RA have targeted these cytokines. While blockade of TNF-alpha or IL-1beta has been efficacious for many patients with RA, adequacy and maintenance of response are not universal, and increased risk of adverse events such as infections and malignancy remain a concern. Therefore, new targets in the treatment of RA continue to be examined. As interleukin-6 (IL-6) has been implicated in the pathogenesis of RA, blockade of its activity is of both scientific and clinical interest. Tocilizumab has been assessed in a number of studies in recent years, mainly in patients with rheumatoid arthritis. Data from randomized controlled clinical trials demonstrate the effectiveness of tocilizumab in improving the signs and symptoms of RA. In addition, it appears that such inhibition of IL-6 can have positive effects on functional status, an important outcome for RA patients. Finally, data suggest that treatment with this agent may also inhibit the progression of disease as assessed radiographically. Data from recent studies will help to refine the ultimate use of this novel approach to treatment, and help clinicians to optimize therapy using this approach.

Di Paola R, Cuzzocrea S. · IRCCS Centro Neurolesi Bonino-Pulejo, Messina, Italy. · Autoimmun Rev. · Pubmed #18708167 No free full text.

Abstract: Arthritis literally means joint inflammation. Arthritis is not a single disease. Arthritis refers to a group of rheumatic diseases and other conditions that can cause pain, stiffness and swelling in the joints. The forms range from those related to wear and tear of cartilage (such as osteoarthritis) to those associated with inflammation resulting from an overactive immune system (such as rheumatoid arthritis). Arthritis is more heterogeneous and this is an important starting point when discussing animal models for arthritis. Animal models are instrumental in understanding the etiology and pathogenetic mechanisms of rheumatoid arthritis. Several new mouse models have either been produced. Various methods have been applied to induce in animals experimental models of arthritis which would provide important insights into the aetiopathogenetic mechanisms of human RA.