Etiopatogenia Gota

Etiopatogenia GotaIgnacio Alfredo Valerio MoralesMdico Residente en ReumatologaMetabolismo de las purinas

Catabolismo y Salvamento de los Nucletidos de Purina:

1.- El catabolismo de los nucletidos de purina conduce en ltima instancia a la produccin de cido rico que es insoluble y es excretado en la orina como cristales de urato de sodio.2.- La sntesis de los nucletidos desde las bases de purina y de los nuclesidos de purina ocurre en una serie de pasos conocidos como vas de salvamento. 3.- Las bases libres de purina, adenina, guanina, e hipoxantina, pueden ser reconvertidas a sus correspondientes nucletidos mediante fosforibosilacin. Dos enzimas transferasas importantes estn implicadas en el salvamento de las purinas: adenosin fosforibosil transferasa (APRT), que cataliza la siguiente reaccin:adenina + PRPP AMP + Ppiy, la hipoxantina-guanina fosforibosil transferasa (HGPRT), que cataliza las siguientes reacciones:hipoxantina + PRPP IMP + Ppiguanina + PRPP GMP + Ppi3.- Una crtica importante de la enzima purina salvamento en clulas de rpida divisin es la adenosina deaminasa (ADA), que cataliza la deamination de adenosina a inosina. 4.- La deficiencia de ADA en los resultados en el llamado trastorno grave inmunodeficiencia combinada, SCID (y brevemente se exponen a continuacin)5.- Los cido nuclicos ya existentes en el organismo son hidrolizados por endo y exonucleasas que dan mononucleosidos por la Fosfomonoestearasa, enzima que libera guanosina y adenosina. Estos 2 nucleotidos pueden seguir la misma via de degradacin.6.- XANTINO OXIDASA: Desde la hipoxantina y la guanina, como bases pricas se forma un compuesto llamado xantina que da origen al cido rico. Estos ltimos dos pasos son catalizados por la xantina oxidasa (enzima que contiene FA, molibdeno y Hierro no Hem) La actividad de la xantino oxidasa da lugar a la formacin de cido rtico y luego al urato monosdico.7.- FORMACION DE CIDO URICO: La degradacin de purinas da lugar a cido rico. AMD se desamina para producir IMP (Msculo) AMP se hidroliza para producir adenosina (Resto de los tejidos)3

http://themedicalbiochemistrypage.org/

http://themedicalbiochemistrypage.org/1.- Los problemas clnicos asociados al metabolismo del nucletido en humanos son predominantemente el resultado del catabolismo anormal de las purinas. 2.- Las consecuencias clnicas del metabolismo anormal de purina se extienden de desordenes medios a severos e incluso fatales. 3.- Las manifestaciones clnicas del catabolismo anormal de purina se presentan desde la insolubilidad del producto derivado de la degradacin, cido rico. 4.- La Gota es una condicin que resulta de la precipitacin del urato como cristales monosdicos de urato (MSU) o de dihidrato pirofosfato de calcio (CPPD) en el lquido sinovial de las articulaciones, conduciendo a inflamacin severa y a artritis. La respuesta inflamatoria se debe a la reaccin de los cristales con un sistema inflamatorio lo que resulta en la produccin de interleucina-1 (IL-1) y IL-18. 5.- La mayora de las formas de gota son el resultado del exceso en la produccin de purina y del catabolismo consiguiente o, a una deficiencia parcial en de la enzima de salvamento, HGPRT.

6.- Dos desrdenes severos, ambos absolutamente bien descritos, estn asociados con defectos en el metabolismo de purina: El Sndrome de Lesch-Nyhan y la enfermedad de inmunodeficiencia severa combinada (SCID). 6.1.- El sndrome de Lesch-Nyhan resulta de la prdida del gen HGPRT funcional. El desorden es heredado como rasgo ligado al sexo, con el gen HGPRT en el cromosoma X (Xq26q27.2). Los pacientes con este defecto exhiben no slo sntomas severos de gota sino tambin un severo malfuncionamiento del sistema nervioso. En los casos ms severos, los pacientes recurren a la auto mutilacin. La muerte generalmente ocurre antes que los pacientes alcancen su vigsimo ao.

7.- La SCID es ms frecuentemente causada (90%) por una deficiencia en la enzima adenosin deaminasa (ADA). sta es la enzima responsable de convertir la adenosina a la inosina en el catabolismo de las purinas. Esta deficiencia conduce selectivamente a una destruccin de los linfocitos B y T, las clulas que sientan las bases de las respuestas inmunes. En ausencia de ADA, la deoxiadenosina es fosforilada para producir niveles de dATP que son 50 veces ms altos que lo normal. Los niveles son especialmente altos en los linfocitos, que tienen cantidades abundantes de enzimas de salvamento, incluyendo nucleosidocinasas. Las altas concentraciones de dATP inhiben la ribonucletido reductasa (vase abajo), de tal modo que evita que otros dNTPs sean producidos. El efecto neto es de inhibir la sntesis de DNA. Puesto que los linfocitos pueden ser capaces de proliferarse dramticamente en respuesta al reto antignico, la inhabilidad para sintetizar DNA deteriora seriamente las respuestas inmunes, y la enfermedad es generalmente fatal en la infancia a menos que se tomen especiales medidas protectoras. Una inmunodeficiencia menos severa resulta cuando hay una carencia de purina nucletido fosforilasa (PNP), otra enzima degradante de purina.

8.- Una de las muchas enfermedades de almacenamiento de glicgeno la enfermedad de von Gierke tambin conduce a la produccin excesiva de cido rico. Este desorden resulta de una deficiencia en la actividad de la glucosa 6-fosfatasa. El incremento en la disponibilidad de glucosa-6-fosfato aumenta el rango del fluido a travs de la va de la pentosa fosfato, produciendo una elevacin en el nivel de ribosa-5-fosfato y por lo tanto de PRPP. Los incrementos en PRPP entonces resultan en exceso de la biosntesis de purina.5

Acido rico: Vas de produccin1.- The de novo synthesis starts with 5-phosphoribosyl 1-pyrophosphate (PRPP), which is produced by addition of a further phosphate group from adenosine triphosphate (ATP) to the modified sugar ribose-5-phosphate. 2.- This step is performed by the family of PRPP synthetase (PRS) enzymes. In addition, purine bases derived from tissue nucleic acids are reutilized through the salvage pathway. 3.- The enzyme hypoxanthineguanine phosphoribosyl transferase (HPRT) salvages hypoxanthine to inosine monophosphate (IMP) and guanine to guanosine monophosphate (GMP). Only a small proportion of patients with urate overproduction have the well-characterized inborn errors of metabolism, such as superactivity of PRS and deficiency of HPRT. 4.- Furthermore, conditions associated with net ATP degradation lead to the accumulation of adenosine diphosphate (ADP) and adenosine monophosphate (AMP), which can be rapidly degraded to uric acid. These conditions are displayed in left upper corner. Plus sign denotes stimulation, and minus sign denotes inhibition. APRT adenine phosphoribosyl transferase; PNP purine nucleotide phosphorylase.6Acido ricocido Dbil pKa 5.8Lmite de Solubilidad 380mmol/LSolubilidad en Sol Fisiolgica a 37C 6,8mg/100mlA 30 baja a 4,5mg/100mlFormas Ionizadas corresponden a Sal98% MSUDepsitos tisulares MSU, clculos de cido ricoSlo 4-5% unido a protenas

http://themedicalbiochemistrypage.org/Ausencia de Uricasa en HumanosHumano nico mamfero que desarrolla gota de manera espontnea.Degradacin oxidativa ausenteConcentraciones de urato en plasma 10x en humano en comparacin con otras especiesUrato antioxidante = Vit CVentaja evolutiva?Ann Intern Med. 2005;143:499-516.

Humans are the only mammals in whom gout is known to develop spontaneously, probably because hyperuricemia only commonly develops in humans (5). In most fish, amphibians, and nonprimate mammals, uric acid that has been generated from purine (see Glossary) metabolism undergoes oxidative degradation through the uricase enzyme, producing the more soluble compound allantoin. In humans, The uricase gene is crippled by 2 mutations that introduce premature stop codons (see Glossary) (6). The absence of uricase, combined with extensive reabsorption of filtered urate, results in urate levels in human plasma that are approximately 10 times those of most other mammals (30 to 59 mol/L) (7). The evolutionary advantage of these findings is unclear, but urate may serve as a primary antioxidant in human blood because it can remove singlet oxygen and radicals as effectively as vitamin C (8). Of note, levels of plasma uric acid (about 300 M) are approximately 6 times those of vitamin C in humans (8, 9). Other potential advantages of the relative hyperuricemia in primate species have been speculated . However, hyperuricemia can be detrimental in humans, as demonstrated by its proven pathogenetic roles in gout and nephrolithiasis and by its putative roles in hypertension and other cardiovascular disorders.8Balance de Uratohttp://themedicalbiochemistrypage.org/cul es el problema?

Ann Intern Med. 2005;143:499-516.Hiperuricemia

2/3 Urato Renal

1/3 Extrarrenal (G.I.)

Rin principal regulador de niveles de Acido rico srico

Ichida, K. et al. Nat. Commun. 3:764 (2012)1.- hyperuricemia induces gout and kidney stones and accelerates the progression of renal and cardiovascular diseases. Unlike other mammals, hominoids, including humans, show high serum uric acid levels (SUAs), because uric acid (urate) is the end product in the purine metabolism owing to the lack of the urate-degrading enzyme uricase3. 2.- It is commonly accepted that two-thirds of the urate is excreted from the kidney into urine via the renal excretion pathway, and the remaining third via the extra- renal excretion pathway, such as gut excretion. 3.- Hyperuricemia has been clinically classified into the urate overproduction type, the underexcretion type, and the combined type. This classification is, however, based solely on the amount of renal urate excretion and urate clearance69, and extra-renal excretion, for example, via the gut excretion pathway, is not considered. 4.- El Rin cuenta con mecanismos complejos de excrecin, reabsorcin y secrecin de urato que regula su concentracin srica en el organismo.

Figura: Current classification of hyperuricemia. Classification of hyperuricemia is based on uuE and fractional excretion of urate (FEuA).In this study, patients were classified as overproduction hyperuricemia, when their uuE was over 25.0 mg h 1/1.73 m2 (600 mg per day/1.73 m2). Those who had FEuA under 5.5% were classified as underexcretion hyperuricemia. Combined type was classified when their uuE and FEuA met the criteria of both overproduction and underexcretion hyperuricemia. Patients who met the single criterion of overproduction hyperuricemia, excluding combined type, were defined as overproduction type. In addition to the types shown in this figure, there is a normal type whose uuE is 25 mg h 1/1.73 m2 and FEuA is 5.5%. uuE unit, mg h 1/1.73 m2

11Eliminacin y excrecin de AU

McLean L, et al. Hochberg MC, editors.In:Rheumatology. 2008. p. 1813-26.Filtracin glomerular.Reabsorcin.Secrecin.Reabsorcin.Gaffo AL, et al. Am Journal of Kidney Dis.2008;52:994-1009.Mecanismos Renales NormalesEl TransporteosomaGLUT-9 (SCL2A9), URAT1 (SLC22A12)Transportadores de cido orgnicosMiembros 6,8,11,13 Familia 22 de acarreadores de solutos (OAT1, OAT3, OAT4, ORCTL-3)MRP4 (multidrug-resistance-associated protein 4)SLC5A8, SLC5A12, ABCG2 Protenas PDZK1 (determinante gentico)

Reginato, A. M. et al. Nat. Rev. Rheumatol. 8, 610621 (2012);

URAT1: ReabsorbeSLC22A12: SecretahUAT1: SecretaOAT: Reabsorcin y secrecin

The uric acid transportasome. Urate transporters in renal proximal tubules are involved in the secretion and reabsorption of urate. The balance between these processes determines the net proximal renal excretion. Urate secretion involves SLC22A6 and SLC22A8, which transport uric acid into the epithelial cell across the basolateral membrane, and URAT1, SLC22A13, SLC17A1, SLC17A3, MRP4 and ABCG2, which transport uric acid out of the epithelial cell across the apical membrane. Reabsorption of urate across the apical membrane involves the urate-anion exchangers URAT1 and SLC22A13, which facilitate the entry of urate into the cell in exchange for monocarboxylates (transported into the cellby the sodium-dependent transporters SCL5A8 and SCL5A12) as well as SLC22A11, which exchanges urate and dicarboxylates (transported into the cell by SLC13A3). Antiuricosuric drugs can serve as the exchanging anion for URAT1 and, therefore, enhance urate transport. URAT1 is inhibited by uricosuric agents and might be regulated by hormones. The glucose transporter GLUT-9 also has an important role in reabsorption of urate; GLUT-9b transports uric acid across the apical membrane and GLUT-9a transports uric acid out of the epithelial cell across the basolateral membrane. The scaffolding protein, PDZK1, is involved in the assembly of a transport complex in the apical membrane.13

Reginato, A. M. et al. Nat. Rev. Rheumatol. 8, 610621 (2012);Mecanismos Renales NormalesFigure 1 Model of urate handling in the proximal tubule of the kidney. Resorption (solid black arrows) and secretion (dashed black arrows) are carried out by organic anion transporters (OATs) and other transporters. (Gray arrows indicate anion or cation transport partners.) URAT1, an organic anion transporter, has been identified as a key urate transporter for resorption and is the target of proben- cid and other uricosuric agents. Other resorbing transporters (e.g., OAT4 and OAT10) also move urate from the tubular lumen into the cell. Glut9a, on the basolateral aspect of tubular epithelial cells, moves urate from the cell to the interstitium; its activity depends on membrane potential. Important transporters for urate secretion include ABCG2, MRP4, NPT1, and NPT4 on the luminal side, and OAT1 and OAT3 on the basolateral side. Deficiencies in ABCG2 may be of particular importance in hereditary urate underexcretion.14Mecanismos Renales Anormales

Principales Transportadores ligados a la regulacin de niveles sricos de Urato-Reabsorcin apical de urato Regulada por SLC22A12ABCG2 y SCL17A1 median secrecin apical de urato. Facilitador de transporte de hexosas SLC2A9 transporta urato (reabsorbe) mediante transporte dependiente de voltaje-aniones.

Ichida, K. et al. Nat. Commun. 3:764 (2012)Mutations in renal urate transporters that are associated with gout.The principal transporters in the current model of bidirectional urate anion movement in proximal tubule epithelial cells are shown. The balance between urate reabsorption and secretion is critically linked to net uric acid elimination in urine. This schematic shows the major transporters that are linked with serum urate levels and susceptibility to gout in genetic studies; other transporters at the apical and basolateral membrane (ABCC4 and SLC22A11, not shown) are also implicated in urate disposition. - Urate reabsorption at the apical membrane is critically regulated by SLC22A12-mediated exchange of urate for intracellular organic anions (for example, lactate, nicotinate) and monocarboxylates (for example, pyrazinamide metabolites). The purine nucleoside transporter ABCG2 and the voltage-driven transporter SLC17A1 mediate urate secretion at the apical membrane. The hexose transport facilitator SLC2A9 carries out voltage-dependent urate anion transport, which at the basolateral membrane leads to urate reabsorption into the circulation. Some evidence also indicates a role for SLC2A9 at the basolateral membrane in reabsorption of urate anion in proximal tubule cells. Importantly, the uricosuric drugs probenecid and benzbromarone inhibit both SLC22A12 and SLC2A9. Abbreviations: ABC, ATP-binding cassette family member; SLC, solute carrier family member.15HiperuricemiaNueva clasificacin.

Ichida, K. et al. Nat. Commun. 3:764 (2012)

Etiopatogenia: Hiperuricemia-Gota Bases GenticasReginato, A. M. et al. Nat. Rev. Rheumatol. 8, 610621 (2012);

Reginato, A. M. et al. Nat. Rev. Rheumatol. 8, 610621 (2012);Etiopatogenia: Hiperuricemia-Gota Bases Genticas

Reginato, A. M. et al. Nat. Rev. Rheumatol. 8, 610621 (2012);Etiopatogenia: Hiperuricemia-Gota Bases Genticas

Reginato, A. M. et al. Nat. Rev. Rheumatol. 8, 610621 (2012);Etiopatogenia: Hiperuricemia-Gota Bases GenticasThe common genetic variants identified in GWAS confer a modest risk of gout. However, an additive com- posite genetic urate score of high-risk alleles can confer up to a 41-fold increased risk for gout compared with individuals without any such alleles.33 A similarly con- structed nongenetic risk factor score (based on BMI, alcohol intake, diuretic use and history of hypertension) conferred up to a 79-fold increased risk of gout in the US general population.98 The serum uric acid variance explained by common genetic variants is small (~6% in the CHARGE meta-analysis),33 particularly when compared with the 67% of serum uric acid variance that can be explained by nongenetic factors, such as serum creatinine level, metabolic syndrome components (including insulin resistance, waist circumference and systolic blood pressure) and FEua.75The clinical utility of genetic variants or their compo- site genetic scores for gout remains unclear. Their utility for predicting gout seems limited because serum urate levels, which can be easily measured, effectively predict gout risk.2 Furthermore, genetic scores would have limited utility in justifying initiation of urate-lowering therapy in patients with asymptomatic hyperuricaemia37 because even onset of gout does not necessarily justify initiation of such therapy given the associated potential adverse effects.99,100 Further studies are required to determine if genetic scores could be used to predict worse outcomes, such as tophaceous erosive gout, complica- tions of gout, or responses to certain classes of antigout drugs, particularly uricosuric drugs that might target the urate transportasome.20

Etiopatogenia: Hiperuricemia-Artritis GotosaReginato, A. M. et al. Nat. Rev. Rheumatol. 8, 610621 (2012);Etiopatogenia: Obesidad, Resistencia a la Insulina y GotaIMC, ndice cintura-cadera, incremento en peso + incidencia de gota en MasculinosReduccin de peso Reduce niveles sricos de A. Urico Reduccin sntesis de purinas de NovoInsulina exgena reduce excrecin renal de MSU Incrementa la Reabsorcin de MSU dependiente de URAT1Incremento lineal Leptina-UratoResistencia a la insulina Fosforilacin oxidativa deficiente Incremento Acidos grasos libres de cadena larga.Adenosina elevada estimula retencin renal de sodio, urato y agua.

Current Opinion in Rheumatology 2006, 18:193198

Etiopatogenia: Hiperuricemia-Artritis GotosaClin Rheumatol (2012) 31:1321

Etiopatogenia: Hiperuricemia-Artritis GotosaFrmacosEtiopatogenia: Artritis por Depsito de MSU

Clin Rheumatol (2012) 31:1321J Clin Rheumatol 2013;19: 19Y29Respuesta a Cristales de MSU1.- Fagocitosis de MSU por Macrfago2.- Formacin Inflamasoma3.- IL-1B es el pivote inflamatorio que regula la proliferacin celular, diferenciacin y apoptosis en Gota4.- Hallmark Influjo de neutrfilos al tejido sinovial.5.- IL1-R, IL-8 IL-8R, CXCR2 Cruciales para que exista Artritis gotosa6.- Retroalimentacin positiva7.- Cronicidad Tofos - Erosin

El inflamasoma es una protena compleja de alto peso molecular que provee la plataforma para el procesamiento enzimatico de la pro-IL1B inactiva hacia su forma activa IL-1B la cual se excreta de la clula.Los cristales de MSU no pueden SOLO activar/liberar IL-1B de los macrfagos, requieren de la co-estimulacin de Acidos grasos libres i lipopolisacrido (efecto de cerveza o grandes cantidades de carnes)Tofo consiste en cmulos de cristales de cido rico en una matriz de lpidos protenas y lipopolisacridosCon el tiempo el proceso inflamatorio agudo-repetitivo o bien crnico y la presencia de enzimas como metaloproteinasas de matriz, osteoclastos activados producen lesiones oseas erosivas progresivas esto mediado principalmente por IL-125Etiopatogenia: Artritis por Depsito de MSU

Punzi et al. / Autoimmunity Reviews 12 (2012 6671Ann Rheum Dis 2010;69:17381743

Etiopatogenia: Activacin del InflamasomaComposicin (prototipo):Caspasa 1Apoptotic Speck proteinProtein of the nucleotide-binding oligomerisation domainLeucine Repeat and pyrin domain (NLRP)Sustratos: IL-1B, IL-18, IL-33Sensor seales de peligroNLRP1, NLRP3, IPAFInflammasome activation induced by monosodium urate crystals. MSU crystals, once recognized and phagocytosed by cells, interact with the innate immunity receptor NALP3 leading to its activation Consequently, caspase-1 cleaves the inactive pro-IL-1 to the active IL-1. ATP accumulation and reactive oxygen species (ROS) production induced by crystals, also contribute to NALP3 activation.The term inflammasome was coined in 2002 to describe an intracellular proteolytic complex that processes pro-IL-1 (35 kd) to active IL-1 (17 kd form). This complex can have different forms, but the prototypic inflammasome is composed of caspase-1, apoptotic speck protein and a protein of the nucleotide-binding oligomerisation domain, leucine rich repeat and pyrin domain (NLRP) family. Its substrates, apart from IL-1, include IL-18 and possibly IL-33, cytokines that belong to the IL-1 family (reviewed in Martinon et al).29 -The NLRP component is thought to act as a sensor, either of exogenous or endogenous danger signals generated during infection and/or cell stress, to initiate assembly of the complex, eventually leading to dimerisation and activation of the caspases. -To date, three inflammasomes have been identified: the NLRP1, the NLRP3 and the interleukin converting enzyme protease activating factor (IPAF) inflammasome, and in the context of gout and crystal-induced inflam- mation, the NLRP3 inflammasome is the most relevant - Medical interest in the inflammasomes was ignited by the identification of mutations in the NLRP3 gene as the molecular basis of the hereditary -autoinflammatory condition now known as cryopyrin-associated periodic syndromes. -The mutation results in dysregulated IL-1 production due to constitutive activity of the NLRP3 inflammasome, and accounts for clinical features such as fever, arthritis, rash and central nervous sys- tem disease.30 This was confirmed by the results of treatment with IL-1 inhibitors, which effectively controlled the signs and symptoms of the disease.31 32 ***The next major discovery was that MSU and calcium pyrophosphate dehydrate crystals activate macrophages to secrete IL-1 by the NLPR3 inflammasome. In the absence of the components of this complex, secretion of active IL-1 is blocked, suggesting that it may be a regulator of gouty inflammation. A proof-of-concept study using IL-1Ra as an inhibitor showed remarkable effects in acute gout,34 and controlled clinical trials with different inhibitors are ongoing (see below). Current studies implicate inflammasome activation in a remarkable number of different pathologies, ranging from infectious disease to asbestosis and diabetes. These findings will require confirmatory studies in the human disease setting, but suggest that the inflammasome could be involved in myriad disease-associated inflammatory processes.

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Etiopatogenia: Amplificacin infiltracin por Neutrfilos Blancos teraputicosPunzi et al. / Autoimmunity Reviews 12 (2012 6671Ann Rheum Dis 2010;69:17381743Mechanisms of inflammation and IL-1 antagonism in acute gouty arthritis.33 In acute gouty arthritis, phagocytosed MSU crystals activate the NALP3 inflammasome, leading to caspase 1 activation, which in turn leads to cleavage of proIL-1A and secretion of mature IL-1A. Interleukin 1A must bind to both IL-1R1 and IL-1RAcP for signal transduction to occur. In endothelial cells, IL-1A appears to be a major trigger for altered adhesion molecule and chemokine expression, which, together with other inflammatory events, results in neutrophil recruitment that drives the initiation of gouty inflammation. Anakinra binds to IL-1R1, blocking IL-1A and IL-1>; rilonacept acts as a soluble receptor, comprising both IL-1R1 and IL-1RAcP fused to the Fc portion of immunoglobulin G1, neutralizing IL-1A as well as IL-1>; and canakinumab, a monoclonal antibody with IL-1A specificity, neutralizes IL-1A only. Interleukin 1R1 indicates IL-1 receptor type 1; IL-1RAcP, IL-1 receptor accessory protein. Figure reproduced with permission from Neog28Etiopatogenia: Resolucin Espontnea de Gota agudaAclaramiento de cristales de MSU se relaciona con disminucin de inflamacinInhibicin de activacin endotelial y leucocitariaApoptosis de Neutrfilos y otras clulas efectoras Mecanismo fundamental en resolucin del proceso inflamatorioTGF-B Abundante en LS de gota, inhibe la expresin de IL-1 Regulacin a la alza de IL-10 limita inflamacin Cristales MSU inducen PPAR-r en monocitos Promocin apoptosis de neutrofilos y macrfagosInactivacin de mediadores inflamatorios por fijacin de protenas, desensibilizacin cruzada de receptores de citocinas, liberacin de lipoxinas, antagonista de receptor de IL-1.Incremento en permeabilidad vascular local permite entrada de ApoB y E y otras protenas plasmticas que contribuyen a la resolucin de la fase aguda. 3-4 semanasJ Clin Rheumatol 2013;19: 19Y29

J Clin Rheumatol 2013;19: 19Y29Etiopatogenia: Resolucin c/FrmacosFIGURE 1. The most common mechanisms of therapeutic anti-inflammatory action of gouty arthritis drugs. Colchicine, NSAIDs, and glucocorticoids act on many different molecular targets; the mechanisms displayed herein are the most likely targets for reduction of MSU crystalYinduced inflammation when these drugs are administered at the recommended therapeutic doses. AntiYIL-1, IL1-RA, and IL1-TRAP therapies act specifically to block IL-1A.30Etiopatogenia: Desarrollo de Gota Crnica

Ann Intern Med. 2005;143:499-516.PMN en lquido sinovialMastocitosComplemento va clsica y alternaTLR2 y TLR4NALP3Activacin endotelialS100A8, S100A9 , CXCL 8, CXCL 2, IL-8Chronic gouty arthritis typically develops in patients who have had gout for years (Figure 9). Cytokines, che- mokines, proteases, and oxidants involved in acute urate crystalinduced inflammation also contribute to the chronic inflammation, leading to chronic synovitis, carti- lage loss, and bone erosion. Even during remissions of acute flares, low-grade synovitis in involved joints may per- sist with ongoing intra-articular phagocytosis of crystals by leukocytes (136). Tophi on the cartilage surface, which can be observed through arthroscopy (159), may contribute to chondrolysis despite adequate treatment of both hyperuricemia and acute gouty attacks (160). Adherent chondrocytes phagocytize microcrystals and produce active metalloproteinases. Furthermore, crystal chondrocyte cell membrane interactions can trigger chondrocyte activation, gene expression of IL-1 and inducible nitric oxide synthase, nitric oxide release, and the overexpression of matrix metallo- proteinases (see Glossary) that leads to cartilage destruction (161). The crystals can also suppress the 1,25-dihydroxychole- calciferolinduced activity of alkaline phosphatase and osteo- calcin (see Glossary). Thus, crystals can reduce the anabolic effects of osteoblasts, thereby contributing to damage to the juxta-articular bone31Etiopatogenia: Mecanismos de dao articularMecanismos Celulares

El dao articular es una caracteristica distintiva de las artritis erosivas (AR, PsA) lo que ocasiona discapacidad musculoesqueltica, En gota crnica conforme el tamao de los tofos se incrementa y ms articulaciones se ven involucradas existe mayor deformidad y discapacidad. Comparison of bone remodeling in normal and gout-affected bone. a | During a normal bone remodeling cycle, osteoclast-mediated bone resorption is immediately followed by osteoblast-mediated bone formation, enabling the preservation of normal bone mass. b | In a gouty joint, MSU crystals within the tophus evoke a cellular response, associated with reduced osteoblast viability and function and increased osteoclast formation and activity, resulting in localized erosion of bone adjacent to tophus. Abbreviations: M-CSF, macrophage colony-stimulating factor; MSU, monosodium urate; OPG, osteoprotegerin; PGE2, prostaglandin E2.

32Etiopatogenia: Puntos a Recordar