Rheumatoid Arthritis: Spain

Gonzalez-Rey E, Varela N, Chorny A, Delgado M. · Instituto de Parasitologia y Biomedicina Lopez Neyra CSIC, Granada, Spain. · Curr Pharm Des. · Pubmed #17430175 No free full text.

Abstract: The vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two neuropeptides belonging to the VIP/secretin/glucagon family of peptides. VIP/PACAP are present and released from both innervation and immune cells, particularly Th2 cells, and exert a wide spectrum of immunological functions controlling the homeostasis of immune system through different receptors expressed in various immunocompetent cells. VIP/PACAP have a general anti-inflammatory effect, both in innate and adaptive immunity. In innate immunity, VIP/PACAP inhibit the production of pro-inflammatory cytokines and chemokines from macrophages, microglia and dendritic cells. In addition, VIP/PACAP reduce the expression of costimulatory molecules (particularly CD80 and CD86) on the antigen-presenting cells, and therefore reduce stimulation of antigen-specific CD4(+) T cells. In terms of adaptive immunity, VIP/PACAP promote Th2-type responses, and reduce the pro-inflammatory Th1-type responses. Several of the molecular mechanisms involved in the inhibition of cytokine and chemokine expression, and in the preferential development and/or survival of Th2 effectors, are perfectly known. Therefore, VIP/PACAP and analogues have been recently proposed as very promising candidates, alternative to other existing treatments, for treating acute and chronic inflammatory and autoimmune diseases, such as septic shock, rheumatoid arthritis, multiple sclerosis, Parkinson's disease, Crohn disease, or autoimmune diabetes. The aim of this review is firstly to update our knowledge of the cellular and molecular events relevant to VIP function on the immune system; and secondly to gather together recent data that support its role as a type 2 cytokine. Recognition of the central functions VIP plays in cellular processes is focusing our attention on this "very important peptide" as an exciting new candidate for therapeutic intervention and drug development.

Catalina-Fernández I, Alvárez AC, Martin FC, Fernández-Mera JJ, Sáenz-Santamaría J. · Department of Pathology, Hospital Universitario Perpetuo Socorro-Materno Infantil, Badajoz, Spain. · Am J Dermatopathol. · Pubmed #17414439 No free full text.

Abstract: Various dermatoses have been described associated with rheumatoid arthritis. Recently, a specific cutaneous lesion termed "intravascular histiocytosis" has been proposed as a new entity among these dermatoses. We report the case of a 50-year-old woman with rheumatoid arthritis for about 10 years who developed erythematous patches on the extensor surface of lower extremities. Histopathologically, the lesions showed intraluminal proliferation of CD68-positive histiocytes in vessels lined with endothelial cells expressing D2-40, a selective marker for lymphatic endothelium.

Muñoz P, Giannella M, Valerio M, Soria T, Díaz F, Longo JL, Bouza E. · Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, University of Madrid, 28007 Madrid, Spain. · Diagn Microbiol Infect Dis. · Pubmed #17240111 No free full text.

Abstract: Infliximab, a tumor necrosis factor-alpha inhibitor, is increasingly used for the therapy of different inflammatory conditions. We report the first case of cryptococcal meningitis in a patient treated with infliximab and other immunosuppressive agents, and review a further 5 reported cryptococcal infections. All of them involved fungal pneumonia. Outcome was favorable in all cases.

Gilaberte Y, Coscojuela C, Vázquez C, Roselló R, Vera J. · Deapartment of Dermatology, San Jorge General Hospital, Huesca, Spain. · Br J Dermatol. · Pubmed #17223880 No free full text.

Abstract: Perforating dermatoses are characterized by transepithelial elimination of dermal structures. We report a 61-year-old man with rheumatoid arthritis who developed a perforating folliculitis following the administration of two tumour necrosis factor (TNF)-alpha inhibitors, infliximab and etanercept. To our knowledge, no perforating disorders have been reported associated with these drugs. This report suggests, for the first time, a role for TNF-alpha in the pathogenesis of perforating folliculitis.

Gonzalez-Rey E, Delgado M. · Institute of Parasitology and Biomedicine, CSIC, Granada, Spain. · Drug News Perspect. · Pubmed #17080202 No free full text.

Abstract: The induction of immune tolerance is critical for the prevention of autoimmunity and the maintenance of immune homeostasis. The identification of factors involved in the maintenance or restoration of such tolerance has become the focus of new therapies for inflammatory and autoimmune diseases. Cortistatin, a recently discovered cyclic neuropeptide related to somatostatin, has emerged as a potential endogenous antiinflammatory factor based on its production by, as well as its binding to, immune cells. Thus, cortistatin has been found to downregulate the inflammatory response mediated by activated macrophages. The present work reviews various recent studies involving different experimental models of sepsis, rheumatoid arthritis and inflammatory bowel disease, demonstrating that cortistatin treatment offers great benefits at both the clinical and pathological levels. These include the downregulation of both inflammatory and Th1-mediated autoimmune disease components and the emergence of regulatory T cells (Treg) that suppress autoreactive T cells, both of which contribute to the restoration of immune tolerance. While many questions need to be resolved, cortistatin appears to be an exciting and promising candidate for the treatment of several chronic inflammatory diseases and autoimmune disorders.

Orozco G, Rueda B, Martin J. · Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas (CSIC), Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento s/n 18100 Armilla, Granada, Spain. · Biomed Pharmacother. · Pubmed #17055211 No free full text.

Abstract: Rheumatoid arthritis (RA) is a clinically heterogeneous condition with a complex aetiology in which environmental and genetic factors are implicated. The contribution of human leukocyte antigen (HLA) genes, particularly the HLA-DRB1 gene, to RA genetic predisposition was the first described, and remains as the best characterised single genetic risk factor contributing to RA. However, it has been estimated that only 30% of the genetic contribution to RA can be attributed to HLA genes and it is suggested that other non-HLA genes may play a relevant role in RA susceptibility. Linkage studies and association studies are the two main strategies used in the investigation of genetic factors contributing to complex genetic traits. In this work we review the progress made in the field of RA genetics, focusing mainly on the contribution of candidate gene association studies to the dissection of RA genetic risk factors.

Gonzalez-Gay MA, Gonzalez-Juanatey C, Miranda-Filloy JA, Garcia-Porrua C, Llorca J, Martin J. · Rheumatology Division, Hospital Xeral-Calde, c/Dr. Ochoa s/n, 27004 Lugo, Spain. · Biomed Pharmacother. · Pubmed #17049201 No free full text.

Abstract: Epidemiological studies have disclosed an increased mortality due to cardiovascular (CV) complications in patients with rheumatoid arthritis (RA). Patients with this disease have an increased risk of left ventricular diastolic dysfunction and congestive heart failure that is unrelated to the presence of traditional atherosclerosis risk factors or ischemic heart disease. Endothelial dysfunction, an early step in the atherogenesis process, is observed in both early and long-standing actively treated patients with RA. High-resolution B-mode ultrasound studies of the common carotid artery have shown the presence of subclinical atherosclerosis, manifested by increased carotid intima-media thickness and carotid plaques, in patients with RA. Association between HLA-DRB1*04 shared epitope alleles, in particular with HLA-DRB1*0404, and endothelial dysfunction and CV mortality has also been observed in these patients. Chronic inflammation plays a pivotal role in the mechanisms associated with atherogenesis in RA. Tumor necrosis factor (TNF)-alpha is a potent proinflammatory cytokine implicated in the initiation and progression of inflammation as well as in the mechanisms associated with accelerated atherosclerosis in this disease. Anti-TNF-alpha therapy has proved to be clinically effective in patients with severe RA. Recent studies have also emphasized the positive effect of anti-TNF-alpha blockade in improving endothelial dysfunction in RA patients. However, this effect seems to be transient and in line with the persistence of chronic inflammation.

García-Carrasco M, Fuentes-Alexandro S, Escárcega RO, Salgado G, Riebeling C, Cervera R. · Systemic Autoimmune Disease Research Unit, HGZ #36 CMN Manuel Avila Camacho, IMSS, Puebla, Mexico. · Arch Med Res. · Pubmed #17045106 No free full text.

Abstract: The term Sjögren's syndrome refers to keratoconjunctivitis sicca and xerostomia due to lymphocytic infiltrates of lachrymal and salivary glands. The current used criteria for diagnosis of primary Sjögren's syndrome is the American-European consensus. Primary Sjögren's syndrome is an autoimmune disorder characterized by lymphocytic infiltrates and destruction of the salivary and lachrymal glands and systemic production of autoantibodies to the ribonucleoprotein particles SS-A/Ro and SS-B/La. The infiltrating cells (T- and B-cells, dendritic cells) interfere with glandular function at several points: destruction of glandular elements by cell-mediated mechanisms; secretion of cytokines that activate pathways bearing the signature of type 1 and 2 interferons; production of autoantibodies that interfere with muscarinic receptors; and secretion of metalloproteinases (MMPs) that interfere with the interaction of the glandular cell with its extracellular matrix, which is necessary for efficient glandular function. As the process progresses, the mucosal surfaces become sites of chronic inflammation and the start of a vicious circle. Despite extensive study of the underlying cause of Sjögren's syndrome, the pathogenesis remains obscure. In broad terms, pathogenesis is multifactorial; environmental factors are thought to trigger inflammation in individuals with a genetic predisposition to the disorder.

Jimenez-Caballero PE, Diamantopoulos-Fernandez J, Camacho-Castaneda I. · Hospital Virgen de la Salud, Complejo Hospitalario de Toledo, 45005 Toledo, Espana. · Rev Neurol. · Pubmed #17033980 links to  free full text

Abstract: INTRODUCTION: Hypertrophic pachymeningitis is an infrequent disease that is characterised by inflammatory hypertrophy of the dura mater. There are cranial, spinal and craniospinal forms of the disease. They may be due to underlying infectious, autoimmune or neoplastic processes, although most of the cases reported in recent years have no base pathology and are known as idiopathic hypertrophic pachymeningitis. The ideal treatment is unknown, but most cases usually respond well to therapy with corticoids. CASE REPORTS: We report two cases of cranial forms, one idiopathic with typical clinical features consisting in cranial polyneuropathy and good response to corticoids, and another case secondary to rheumatoid arthritis that began with epileptic seizures. Both had a parenchymatous oedema. The two forms of spinal pachymeningitis presented as progressive paraparesis that evolved well after surgical removal of the lesion. CONCLUSIONS: On observing pachymeningitis in neuroimaging tests it becomes necessary to conduct a comprehensive aetiological study in search of infectious, autoimmune and neoplastic diseases. In the cranial forms there may be parenchymatous oedema, which would explain the epileptic seizures and the cognitive deterioration of our patients. Response to corticoids is spectacular, although it is often necessary to continue to administer them for prolonged periods of time.

Paul-Pletzer K. · Medical Information Department, Prous Science, Barcelona, Spain. · Drugs Today (Barc). · Pubmed #17028666 No free full text.

Abstract: Interleukin (IL)-6 contributes to a myriad of physiologic and pathophysiologic processes. Among its many physiologic functions, IL-6 plays an active role in immunology, inflammatory responses, bone metabolism, arthritis and neoplasia. Overproduction of IL-6 has been implicated in the disease pathology of several inflammatory and autoimmune disorders, including rheumatoid arthritis, Castleman's disease, Crohn's disease and systemic-onset juvenile idiopathic arthritis. Interception of the IL-6 signaling pathway could thus represent a new treatment option for these diseases, given their refractory status to conventional therapy. Clinical studies with tocilizumab, a humanized monoclonal anti-IL-6 receptor antibody, have been undertaken to explore this option. Current short-term results indicate that tocilizumab dramatically improves disease activity and is well tolerated. Further long-term safety and efficacy studies are needed to confirm the therapeutic benefit of this antibody in inflammatory and autoimmune disorders.

Ariza-Ariza R, Navarro-Sarabia F, Hernández-Cruz B, Rodríguez-Arboleya L, Navarro-Compán V, Toyos J. · Rheumatology Service, Hospital Universitário Virgen Macarena, Seville, Spain. · Rheumatology (Oxford). · Pubmed #17012439 links to  free full text

Abstract: OBJECTIVE: To estimate the proportion of rheumatoid arthritis (RA) patients on anti-tumour necrosis factor (anti-TNF) who require dose escalation. METHODS: Systematic review of the scientific literature. Infliximab, etanercept and adalimumab studies in RA were considered. Primary outcome was the proportion of patients requiring dose escalation. American College Rheumatology (ACR) and Disease activity score (DAS) responses post-escalation were assessed when available. RESULTS: From 1801 references, 16 studies with 8510 patients were included. Of all the infliximab patients, 53.7% underwent dose escalation. Fourty-four per cent of the infliximab patients experienced dose increase and 8.3%, frequency increase. The ACR20 response to dose escalation ranged from 27 to 36% and DAS28 improved from 5.2 to 4.5 in one study and from 4.1 to 3.7 in another. Of the etanercept patients, 17.5% experienced a dose increase but changes on the mean dose were not statistically significant. CONCLUSIONS: Dose escalation is common in patients treated with infliximab, and less frequent with etanercept. In a proportion of patients, the dose escalation seems effective. The design and evidence level of the available studies limit the strength of the conclusions.

Ramos-Casals M, Brito-Zerón P, Font J. · Department of Autoimmune Diseases, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain. · Semin Arthritis Rheum. · Pubmed #16996579 No free full text.

Abstract: OBJECTIVE: To analyze the main diagnostic problems caused by the overlap between Sjögren's syndrome (SS) and other systemic autoimmune diseases (SAD). METHODS: We performed a MEDLINE search for articles published between January 1966 and December 2005 that specifically analyzed the overlap between SS and other SAD. We identified a list of diagnostic problems in patients with primary SS who had features considered typical of other SAD. RESULTS: Clinically, the main diagnostic problems occur in SS patients presenting with arthritis, Raynaud phenomenon, cutaneous features (subacute cutaneous lupus erythematosus, purpura, livedo reticularis, erythema nodosum), interstitial pulmonary disease, and cytopenias (leukopenia, thrombocytopenia). Immunologically, antiphospholipid antibodies (aPL) and antineutrophil cytoplasmic antibodies (ANCA) are the most frequent atypical autoantibodies found in primary SS, with a prevalence ranging between 10 and 20%. However, coexisting antiphospholipid syndrome or systemic vasculitis is only detected in around 10% of SS patients with aPL or ANCA. Anti-DNA and anticentromere antibodies have a prevalence of 5 to 10%, but are more closely related to clinical and/or laboratory data suggestive of associated systemic lupus erythematosus and limited systemic sclerosis, respectively, leading to the fulfillment of classification criteria for these diseases in more than 25% of cases. CONCLUSION: The wide variety of clinical and immunological manifestations of patients with primary SS often overlap with other SAD, making the differentiation between primary SS, SS associated with SAD, and SS-like presentations of some other SAD difficult. This overlap suggests that the current classification criteria are useful in differentiating between autoimmune and non-autoimmune processes but fail to clearly differentiate among SAD.

Perez J. · Department of Anesthesia, Chronic Pain Unit, Hospital Clinic de Barcelona, Barcelona, Spain. · Drugs Today (Barc). · Pubmed #16969427 No free full text.

Abstract: Extensive basic science research has identified the potential therapeutic benefits of active compounds extracted from the Cannabis sativa L. plant (the cannabinoids). It is recognized that a significant proportion of patients suffering with the debilitating symptoms of pain and spasticity in multiple sclerosis or other conditions smoke cannabis despite the legal implications and stigma associated with this controlled substance. GW Pharmaceuticals have developed Sativex (GW- 1,000-02), a combined cannabinoid medicine that delivers and maintains therapeutic levels of two principal cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), via an oromucosal pump spray, that aims to minimize psychotropic side effects. Sativex has proved to be well tolerated and successfully self-administered and self-titrated in both healthy volunteers and patient cohorts. Clinical assessment of this combined cannabinoid medicine has demonstrated efficacy in patients with intractable pain (chronic neuropathic pain, pain due to brachial plexus nerve injury, allodynic peripheral neuropathic pain and advanced cancer pain), rheumatoid arthritis and multiple sclerosis (bladder problems, spasticity and central pain), with no significant intoxication-like symptoms, tolerance or withdrawal syndrome.

Chorny A, Gonzalez-Rey E, Varela N, Robledo G, Delgado M. · Instituto de Parasitologia y Biomedicina, CSIC, Avd. Conocimiento, PT Ciencias de la Salud, Granada 18100, Spain. · Regul Pept. · Pubmed #16949684 No free full text.

Abstract: The vasoactive intestinal peptide (VIP) is a neuropeptide belonging to the secretin/glucagon family of peptides, which exerts a wide spectrum of immunological functions controlling the homeostasis of immune system through different receptors expressed in various immunocompetent cells. In the last decade, VIP has emerged as a potent anti-inflammatory factor, which exerts its function by regulating the production of both anti- and pro-inflammatory mediators. In this sense, VIP has been proposed as a promising candidate, alternative to other existing treatments, for treating acute and chronic inflammatory and autoimmune diseases, such as septic shock, rheumatoid arthritis, multiple sclerosis and Crohn's disease. The present work reviews the involvement of the specific receptors and or different transduction pathways and transcription factors in the anti-inflammatory action of VIP, and their implication on its therapeutic effect on inflammatory/autoimmune disorders.

Pousa ID, Gisbert JP, Maté J. · Servicio de Gastroenterología y Hepatología. Hospital Universitario de la Princesa. Madrid. España. · Gastroenterol Hepatol. · Pubmed #16938258 No free full text.

Abstract: There are 4 major concepts in vascular development: vasculogenesis (formation of blood vessels from angioblasts), angiogenesis (formation of vascular sprouts from preexisting vessels), arteriogenesis (thickening and development of vessels) and lymphangiogenesis (formation of lymphatic vessels). In the last decade, these concepts, especially angiogenesis and lymphangiogenesis, have acquired major importance due to their role in tumoral growth and metastatic dissemination. Moreover, the activity of various diseases that involve chronic inflammation, such as asthma, psoriasis and rheumatoid arthritis, has been associated with vascular development. Several growth factors and cytokines are involved in this process and consequently investigation into these elements, both in peripheral blood and their expression in affected tissues, could elucidate the role of vascular development in diseases whose pathogenesis involves chronic inflammation, such as inflammatory bowel disease. The presence of distinct molecules involved in vascular development processes, such as vascular endothelial growth factor (VEGF), basic fibroblastic growth factor and placental growth factor, among others, has been studied in both ulcerative colitis and Crohn's disease, although not extensively. It has been suggested that the phenomena of vasculogenesis, angiogenesis and lymphangiogenesis play a critical, although not exclusive, role in the inflammation that characterizes inflammatory bowel disease. In general, the results obtained to date suggest that new vascular formation is involved in the pathogenesis of these diseases.

Gomariz RP, Juarranz Y, Abad C, Arranz A, Leceta J, Martinez C. · Department of Cell Biology, Faculty of Biology, Complutense University, 28040 Madrid, Spain. · Ann N Y Acad Sci. · Pubmed #16888149 No free full text.

Abstract: Our research about VIP/PACAP and the immune system goes back to 1990 when our group described the expression of VIP on lymphocytes for the first time. Since this year, using three models of disease, septic shock, rheumathoid arthritis, and Crohn's disease, we are trying to contribute with new pieces to the puzzle of immunity to approach the use of VIP/PACAP system as a therapeutic agent. In 1999 we established that the first step in the beneficial effect of the VIP/PACAP system exerts consists in its potent anti-inflammatory action. Thus, VIP and PACAP inhibit the expression and release of proinflammatory cytokines and chemokines, and enhance the production of the anti-inflammatory factors. These effects were reported both in vitro and in vivo, are mediated by the presence of PAC1, VPAC1, and VPAC2 receptors, in the three models of diseases used. The next step was that the system favors Th2 responses versus Th1 contributing to the remission of illness as rheumatoid arthritis or Crohn's disease by blocking the autoimmune component of these diseases. Because it appears that inflammatory processes requires more than blockade of a single mediator, new therapies blocking several components of both the infection- and the autoimmunity-induced inflammation cascades should be an interesting focus of attention. In this sense, at present we are trying to dissect new aspects of the potential therapeutic of the VIP/PACAP system in the control of CC and CXC chemokine and their receptors, coagulation factors, adhesion molecules, acute phase proteins, and osteoclastogenesis mediators as well as in the modulation of the expression of Toll-like receptors. Our more recent data open a hopeful door for the therapeutic use of VIP/PACAP in humans.

Sánchez Carazo JL, Mahiques Santos L, Oliver Martinez V. · Servicio de Dermatologia, Consorcio Hospital General Universitario, Valencia, Spain. · Drug Saf. · Pubmed #16872241 No free full text.

Abstract: Conventional systemic treatments for patients with psoriasis are associated with multiple adverse effects that require continuous monitoring. The introduction of new biological agents such as etanercept, a fully human fusion protein, has permitted individualisation of patients' treatment according to disease stage. The drug is a competitive inhibitor of tumour necrosis factor-alpha (TNFalpha) that prevents interaction between this cytokine and its cell surface receptors. Etanercept also modulates the activity of other inflammatory cytokines and does not induce complement-mediated cell lysis in vitro. The main source of information regarding etanercept safety comes from studies in patients with rheumatoid arthritis. The most common adverse effect during drug administration is mild injection site reactions. There is no increase in the overall incidence of infections compared with placebo, although there have been several reports of infections caused by intracellular organisms (Mycobacterium tuberculosis, Listeria monocytogenes, and Mycobacterium avium intracellulare). Therefore, combination of this drug with corticosteroids must be carefully monitored and should be avoided in patients with established sepsis. There are no data showing that treatment with etanercept results in an increase in the occurrence of malignant neoplasms. However, caution is recommended in use of etanercept in patients with a current or past history of demyelinating disease. Etanercept must be used with extreme caution in patients with heart failure because of several reports indicating a worsening or de novo occurrence of congestive heart failure while receiving the drug. Monitoring of autoantibodies is not currently considered necessary as they do not predict response, toxicity or autoimmune events. The presence of non-neutralising antibodies to the TNF receptor fragment or other protein components of etanercept has not been related to a decrease in drug response or adverse reactions. Etanercept does not generally modify the course of inflammatory bowel disease. When combined with other systemic therapies for psoriasis, current data do not show an increase in adverse events. In patients with hepatitis C viral infection, etanercept does not increase transaminase levels or viral load and in some instances has allowed the concomitant use of interferon which had previously been discontinued because of a worsening of psoriasis. Etanercept is rated as a US FDA category B drug in pregnancy. However, its use is not recommended in pregnant women unless the benefit-risk ratio greatly favours its use. Etanercept is not recommended for use in lactating women. Etanercept represents a relevant treatment for psoriasis, efficacious over many weeks and safe but special care should be taken to avoid the potential risks.

Mesa García MD, Aguilera García CM, Gil Hernández A. · Institute of Nutrition and Food Technology, Department of Biochemistry and Molecular Biology, University of Granada. · Nutr Hosp. · Pubmed #16771071 No free full text.

Abstract: Over the last decades, scientific advances in the knowledge of anti-inflammatory properties of lipids have lead to the development of new formulas for enteral and parenteral nutrition. These products have been utilised as a treatment for a variety of inflammatory diseases. In this review we expose the effects of lipids used in enteral nutriton on different inflammatory pathologies such as inflammatory bowel disease, atherosclerosis, lung fibrosis, rheumatoid arthritis, and others. During inflammatory diseases, eicosanoids are produced from polyunsaturated fatty acids present in cellular membranes. Inflammatory activity of these molecules depends on the nature of their precursors: when arachidonic acid (n-6) is present, pro-inflammatory molecules are released, whereas eicosapentaenoic acid (n-3)-derived eicosanoids are weakly inflammatory. In this way, fish oils, rich in n-3 polyunsaturated fatty acids, increase the content of eicosapentaenoic-eicosanoids and decrease arachidonic acid in immune and endothelial cells leading to a lower inflammatory activity. Likewise, oleic acid exhibits anti-inflammatory effects by preventing the release of particular chemotactic molecules. In summary, enteral diets supplemented with n-3 polyunsaturated fatty acids and oleic acid benefits the treatment of patients with inflammatory pathologies, leading to better outcomes, and decreasing the doses of anti-inflammatory drugs, which exhibit important secondary effects.

Otero M, Lago R, Gomez R, Dieguez C, Lago F, Gómez-Reino J, Gualillo O. · Santiago University Clinical Hospital, Research Laboratory 4 (NEIRID LAB, Laboratory of Neuro Endocrine Interactions in Rheumatology and Inflammatory Diseases), Santiago de Compostela, Spain. · Rheumatology (Oxford). · Pubmed #16720637 links to  free full text

Abstract: Leptin is a 16 kDa adipocyte-secreted hormone that regulates weight centrally and links nutritional status with neuroendocrine and immune function. Since its cloning in 1994, leptin's role in regulating immune and inflammatory response has become increasingly evident. Actually, the increase of leptin production that occurs during infection and inflammation strongly suggests that leptin is a part of the cytokines loop which governs the inflammatory-immune response and the host defence mechanism. Indeed, leptin stimulates the production of pro-inflammatory cytokines from cultured monocytes and enhances the production of Th1 type cytokines from stimulated lymphocytes. Several studies have implicated leptin in the pathogenesis of autoimmune inflammatory conditions such as type 1 diabetes, rheumatoid arthritis and chronic bowel disease. Obesity is characterized by elevated circulating leptin levels which might contribute significantly to the so called low-grade systemic inflammation, making obese individuals more susceptible to the increased risk of developing cardiovascular diseases, type II diabetes or inflammatory articular degenerative disease such as osteorathritis (OA). As a matter of fact, a key role for leptin in OA has been recently demonstrated since leptin exhibits, in synergy with other pro-inflammatory cytokines, a detrimental effect on articular cartilage cells by promoting nitric oxide synthesis. This review will focus prevalently on the complex relationships existing among leptin, inflammatory response and immunity, trying to provide surprising insights into leptin's role and to discuss challenges and prospects for the future.

Navarro-Sarabia F, Ariza-Ariza R, Hernández-Cruz B, Villanueva I. · Rheumatology Service, Hospital Universitario Virgen Macarena, Sevilla, Spain. · J Rheumatol. · Pubmed #16652437 No free full text.

Abstract: OBJECTIVE: To assess the efficacy and safety of adalimumab in the treatment of rheumatoid arthritis (RA). METHODS: A Cochrane systematic review was performed. The literature search, selection and assessment of the methodological quality of the studies, and the data extraction were performed according to the standard methodology of the Cochrane reviews. Outcome measures included American College of Rheumatology (ACR) and European League Against Rheumatism responses, Disease Activity Score 28 and components of the ACR response, and radiographic and safety data. Weighted mean difference and relative risk were used for reporting continuous and dichotomous data, respectively. Number needed to treat (NNT) or to harm (NNH) were estimated when appropriate. When significant heterogeneity was not found, data were pooled. RESULTS: Six studies with 2,390 patients were included in this review. With adalimumab 40 mg every other week (eow) + methotrexate versus placebo + methotrexate, the absolute risk differences to achieve an ACR20, ACR50, and ACR70 response at 52 weeks were 35%, 32%, and 19% with NNT of 2.9, 3.1, and 5.3, respectively. At 52 weeks, adalimumab 40 mg eow and 20 mg every week (ew) significantly slowed the radiological progression. With adalimumab 40 mg eow versus placebo, the absolute risk differences to achieve an ACR20, ACR50, and ACR70 response at 24/26 weeks were 23.64%, 15.31%, and 12.22% with NNT of 5.0, 7.0, and 9.0, respectively. In most of the analyzed studies and comparisons, there were no significant differences in safety outcomes between adalimumab and control groups. CONCLUSION: On the basis of studies reviewed here, adalimumab is efficacious in the treatment of RA. No serious adverse effects occurred.

Rodríguez Moreno C, López Vázquez P, Durán Parrondo C, Tato Herrero F, Lado Lado F, Velasco González M. · Servicio de Farmacología Clínica, Complexo Hospitalario Universitario, Santiago de Compostela, A Coruña. · An Med Interna. · Pubmed #16566659 No free full text.

Abstract: Blockade of tumor necrosis factor with monoclonal antibodies, has emerged as one of the most promising therapies in some autoimmune conditions as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and Crohn's disease. They have shown effectiveness on reducing symptoms and modifying the progression of the disease. However, they disrupt the balance of inflammatory and immune responses and some risks associated with TNF-blockers have become apparent. The purpose of this article is to review the evidence about benefits and risk associated with the use of TNF-blockers in approved indications and to provide practical recommendations for its use in the management of this conditions.

Rodríguez Moreno C, López Vázquez P, Durán Parrondo C, Tato Herrero F, Lado Lado F. · Servicios de Farmacología Clínica, Complexo Hospitalario Universitario, Santiago de Compostela, a Coruña, Spain. carlos.rodrí · An Med Interna. · Pubmed #16542122 No free full text.

Abstract: Blockade of tumor necrosis factor with monoclonal antibodies, has emerged as one of the most promising therapies in some autoimmune conditions as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and Crohn s disease. They have shown effectiveness on reducing symptoms and modifying the progression of the disease. However, they disrupt the balance of inflammatory and immune responses and some risks associated with TNF-blockers have become apparent. The purpose of this article is to review the evidence about benefits and risk associated with the use of TNF-blockers in approved indications and to provide practical recommendations for its use in the management of these conditions.

García-Lechuz Moya JM. · Servicio de Microbiología Clínica y Enfermedades Infecciosas, Hospital General Universitario Gregorio Marañón, Madrid, Spain. · Enferm Infecc Microbiol Clin. · Pubmed #16324568 links to  free full text

Abstract: Treatment with tumor necrosis factor antagonists (anti-TNF) is an innovative therapeutic approach that requires supervised administration by specialists in rheumatology and inflammatory diseases. Collaboration by infectious diseases consultants with expertise in these biological therapies is crucial to detect the development of one of the most frequent and fearsome associated adverse events: infections, particularly, tuberculosis. The tasks of these specialists include screening for tuberculosis prior to anti-TNF therapy, recommending prophylactic measures, detecting latent tuberculosis and avoiding its reactivation, and assessing potential risk and benefits before starting anti-TNF therapy. Moreover, close follow-up of on-treatment patients is mandatory to achieve early diagnosis and treatment of any infectious event caused by bacteria, fungi or mycobacteria.

Ramos-Casals M, Pares A, Jara LJ, Solans R, Viñas O, Vázquez P, Sánchez-Tapias JM, Rodés J, Font J, Anonymous00017. · Department of Autoimmune Diseases, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, School of Medicine, University of Barcelona, Barcelona, Spain. · J Viral Hepat. · Pubmed #16255767 No free full text.

Abstract: To describe the clinical and immunologic patterns of disease expression of patients with chronic hepatitis C virus (HCV) infection and positive antimitochondrial antibodies (AMA). We investigated the presence of AMA in 237 consecutive HCV patients with extrahepatic manifestations from an International Registry. AMA were detected by indirect immunofluorescence in triple rat tissue (liver, stomach and kidney), aceton-fixed criosections and FITC-conjugated rabbit anti-human immunoglobulins. We found positive AMA in 18 (8%) out of 237 HCV patients. All patients were female with a mean age at protocol inclusion of 65.8 years (ranging from 37 to 87 years). Twelve (67%) patients fulfilled classification criteria for systemic autoimmune diseases (SAD), including Sjögren's syndrome (n = 7), systemic sclerosis (n = 3) and systemic lupus erythematosus (n = 2). Fourteen (78%) of the HCV-AMA patients presented at least one of the highly suggestive characteristics of primary biliary cirrhosis (PBC): 9 (50%) had a specific M2 pattern, 6 (33%) had more than twice normal levels of alkaline phosphatase, 5 (28%) had raised IgM levels and 4 (22%) a histological pattern compatible with PBC. Five (28%) patients developed neoplasia after detection of AMA. Seven (39%) patients died, due to neoplasia (n = 4), cirrhotic complications (n = 2) and hepatopulmonary syndrome (n = 1). We describe a subset of HCV patients with positive AMA who presented a broad spectrum of clinical features, including liver, autoimmune and neoplasic manifestations. Two-thirds of these patients presented an associated SAD, mainly Sjögren's syndrome or systemic sclerosis, together with a high frequency of multiple autoantibodies and an increased prevalence of cirrhosis and neoplasia.

Bolós J. · Prous Institute for Collaborative Biomedical Research; Barcelona Science Park, Laboratory P1C41, 08028 Barcelona, Spain. · Mini Rev Med Chem. · Pubmed #16178727 No free full text.

Abstract: Rheumatoid arthritis and other chronic inflammatory diseases constitute a major therapeutic challenge, usually not sufficiently met by the classical antiinflammatory medications. Recent research efforts provided new insights into the molecular basis of these pathologies and disclosed new opportunities for developing improved drugs directed to the chemical mediators of the disease. The enzyme p38 MAP kinase plays a central role in the signal transduction cascade that leads to the production of both the proinflammatory cytokines, TNF-alpha and IL-1 beta, thus representing an attractive therapeutic target for novel antiinflammatory therapies. A number of p38 inhibitors belonging to different structural families have been developed as potential antiinflammatory drugs, and some of them progressed into clinical trials. The initial pyridinyl imidazole inhibitors contributed to the identification and characterization of p38 MAP kinase as the molecular target of these new drugs, and were found to act as competitive inhibitors at the ATP binding site of the enzyme. A number of variations in the pyridine and imidazole rings were subsequently introduced. Other inhibitors structurally unrelated to the pyridinylimidazoles have also been developed, such as the pyridopyridazinones, diaryl ureas, aminobenzophenones and aromatic amides. One of these structural classes, the N,N'-diarylureas, has been found to interact with a distinct allosteric site of p38 MAP kinase and requires a deep conformational change prior to binding.