Miguel Cuchacovich T

El polimorfismo genético del factor de necrosis tumoral alfa como factor de riesgo en patología

Cytokine unbalance is responsible for the pathogenesis of diverse inflammatory, autoimmune and infectious diseases, and Tumor Necrosis Factor Alpha (TNFa), among other cytokines, plays a central role. TNFa production can be regulated at the transcriptional, post-transcriptional, and translational levels. Variability in the promoter and coding regions of the TNFa gene may modulate the magnitude of its secretory response. Up to date, several single nucleotide polymorphisms (SNPs) have been identified in the human TNFa gene promoter. One of these, is a guanine to adenine transition at position -308, that generates the TNF1 and TNF2 alleles, respectively. The TNF2 allele is associated to a high in vitro TNF expression, and it has also been linked to an increased susceptibility and severity, for a variety of illnesses, such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, Alzheimer disease and cerebral malaria among others. It is also associated with a higher septic shock susceptibility and mortality. The investigation of polymorphisms within the TNFa cluster will be important in understanding the role of TNFa regulation in specific diseases (Rev Med Chile 2002; 130: 1043-50).

Papel de los polimorfismos -238 y -308 del promotor del factor de necrosis tumoral alfa en la patogenia y respuesta al tratamiento anti- factor de necrosis tumoral alfa en artritis reumatoide

Rheumatoid arthritis (RA) is a systemic autoimmune disease that affects 0.8% of the world population, it affects the synovial membrane of joints and the clinical presentation encompasses a wide spectrum, ranging from a mild to a severe and erosive disease that causes joint and cartilage destruction which finally provokes irreversible structural damage and patient disability. In the last years, there have been important advances in the pathogenesis of this disease, the efforts have been concentrated on pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFa). This protein guides numerous events in the synovial and systemic inflammatory process and is encoded in the Major Histocompability Complex (MHC), one of the most polymorphic of the genome. Polymorphisms affecting the TNFa gene and its regulatory regions are associated with RA prevalence and course. There is a possible association between these polymorphisms and the clinical response to the use of monoclonal antibodies anti-TNFa. The possibility that the determination of genotypes -238 and -308 may have prognostic and therapeutic consequences is debated nowadays (Rev Med Chile 2005; 133: 1089-95).

Uso del rituximab(anticuerpo monoclonal anti-CD20) en lupus eritematoso sistémico refractario a tratamiento: Caso clínico

New therapeutic approaches that include depletion of B cells usingrituximab, a chimeric monoclonal antibody directed against the B cell specific antigen CD-20have been developed for the treatment of systemic lupus erythematosus (SLE). We report the caseof a 18 years old girl with SLE that did not respond and experienced adverse effects with the useof hydroxycloroquine, methotrexate, mycophenolate mofetil, azathioprine and high-dosesteroids. Rituximab was given weekly at 375 mg/m

Nuevas armas inmunológicas para la medicina del siglo XXI: Terapia biológica basada en el uso de anticuerpos monoclonales de última generación

The fusion of a murine B cell and a myeloma cell generates a hybridoma that produces monoclonal antibody (mAb). These murine mAb induce the HAMA (human anti-mouse antibodies) response. Murine mAb have been modified by genetic engineering, producing molecules with a higher proportion of human protein. At present, chimeric, humanized and fully human mAb are available. mAb block interactions between target molecules and their ligands or trigger the lyses of mAb-coated tumor cells. Numerous mAb have been developed using the recombinant DNA technology and several are available in the market. Trastuzumab, against HER2/neu, is useful in breast cancer; rituximab, against CD20 in B lymphocytes is useful in lymphoma; alemtuzumab, against CD52 is used in lymphoma and leukemia; daclizumab and basiliximab block the IL-2 receptor interaction and reduce acute rejection in kidney transplantion; abciximab, an antagonist of GPIIb/ IIIa platelet receptor, is used in patients undergoing acute coronary syndromes. In autoimmunity diseases, blocking tumor necrosis factor by infliximab and adalimumab has demonstrated excellent results. Thus, infliximab is useful in the treatment of rheumatoid arthritis (RA), Crohn’s disease and ulcerative colitis while adalimumab is the first fully human mAb available for RA. Infliximab and adalimumab reduce signs and symptoms in RA and they also interfere with progression of joint damage. Finally, the direct benefits of antagonist treatment can occur at the expense of a major adverse effect in some other biological function (Rev Med Chile 2003; 131: 1445-53). (Key Words: Antibodies, monoclonal; Tumor necrosis factor)

Características clínicas y respuesta al tratamiento sistémico de la epiescleritis y escleritis primarias y secundarias, refractarias al tratamiento local

Background: Scleritis and episcleritis may extend to adjacent ocular tissues with blinding consequences and may be associated with potentially lethal systemic disorders. Aim: To evaluate the ocular complications and systemic disease associations of the different types of scleritis and episcleritis. Patients and methods: Forty six patients with refractory scleritis and episcleritis were studied and treated during the period 1991 to 1998. Results: Necrotizing type was the most common and severe category in the scleritis group of patients. A decrease in vision occurred in 58.3% of patients with scleritis v/s a 23.5% of patients with epiescleritis (p<0,05). Uveitis was present in 35.4% of patients with scleritis and scleromalacia was present in 33.3% (p<0,05). A specific disease association was uncovered in 51% of scleritis and in 38% of episcleritis patients. Rheumatoid arthritis, primary systemic vasculitic disease and Sjogren syndrome with vasculitis were the most common associated systemic diseases. Three patients with scleritis had tuberculosis. Conclusions: Scleritis is more severe than episcleritis, and necrotizing scleritis is the most severe type of scleritis. Classification of scleritis and episcleritis provides valuable prognostic information. A meticulous approach for the detection of a specific associated disease must be undertaken. Scleritis associated with vasculitis has a worse ocular prognosis than other non infectious diseases. Cyclophosphamide is the most effective inmunosuppresive treatment to control severe ocular involvement (Rev Med Chile 2000; 128: 1205-14)

Terapias emergentes en artritis reumatoide

The use of biological agents such as etanercept, infliximab, adalimumab and anakinra has been recently approved for the treatment of rheumatoid arthritis. All are effective controlling signs and symptoms and inhibiting disease progression. To overcome the problems generated by their high costs and possible participation in reactivating latent infections, other therapeutic tools are being developed. Gene therapy using expression vectors carrying genes coding for specific proteins, may interfere in key points involved in the pathogenesis of the disease. Intra-articular administration of cDNA coding for soluble TNF receptors, IL-1, or IL-1Ra decreases signs of the disease in animal models. Vectors, expressing inhibitors of signal transduction pathways involving to NF-kB and JAK-STAT-3, are effective in modulating joint inflammation in mice. The use of antigen-pulsed antigen presenting cells or dendritic cells (DC) bound to apoptosis-inducing molecules, specifically eliminates autoreactive T cells. Other novel approach attempts the development of T regulatory-inducing tolerogenic DC-based vaccines that inhibit autoreactive T cells, through the secretion of suppressing cytokines or by other mechanisms to be elucidated. Oral tolerance induction to auto-antigens is also a successful experimental strategy under study. Current research aims to control peripheral tolerance in rheumatoid arthritis patients

Crisis de esclerodermia renal.: Rol de la vasculopatía esclerodérmica en la inducción de fibrosis cutáneo-visceral en dos casos

Although fibrosis and vasculopathy coexist in most patients with progressive systemic sclerosis, it is not clear if these events are the result of an unique etiologic factor or if one is consequence of the other. We report two cases of progressive systemic sclerosis that evolved to a renal scleroderma crisis. A 36 years old female presented with a Sjogren syndrome and painful subcutaneous nodules whose biopsy showed perivascular lymphocytic infiltration, perivascular thickening and normal skin. The ESR was 100 mm/h. She developed an hypertensive crisis and progressive renal failure, followed by a rapidly evolving progressive systemic sclerosis. The patient died in the course of this crisis. A 32 years old female with a progressive systemic sclerosis refractory to D-penicillamine treatment, receiving cyclosporin, presented a renal scleroderma crisis, that was successfully treated, with complete recovery of renal function. We highlight the different evolution of these cases, probably due to an early diagnosis and a better experience in the management of this condition. (Rev Med Chile 2000; 128: 86-92)