Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018099 (gout)
 5,192 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gout is due to the formation and tissue deposition of MSU crystals. Hyperuricemia promotes crystal formation and results from the disequilibrium between the synthetic and elimination rates of uric acid. Recent studies have elucidated the mechanisms of renal handling of uric acid by specific transporters (URATI and OAT) which play a role in uric acid excretion. MSU crystals provoke inflammation by activating leukocytes to produce inflammatory cytokines. One mechanism is through the TLR2 and TLR4 receptors, which form part of the innate immune system. MSU crystals can also activate a protein complex called the inflammasome, which in turn activates IL-1 processing to yield the secreted mature form of IL- 1beta. The inflammatory effects of MSU can be blocked by IL-1 inhibitors. These advances could provide new targetted therapeutic approaches to treat hyperuricemia and gout.
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PMID:[Recent advances in the pathophysiology of hyperuricemia and gout]. 1745 49

IL-1beta is a cytokine with major roles in inflammation and innate immune responses. IL-1beta is produced as an inactive proform that must be cleaved within the cell to generate biologically active IL-1beta. The enzyme caspase-1 catalyzes the reaction. Recent work showed that caspase-1 must be activated by a complex known as the inflammasome. The inflammasome comprises NALP, which is an intracellular receptor involved in innate immunity, and an ASC adapter that ensures caspase-1 recruitment to the receptor. The most extensively described inflammasome to date is formed by the NALP3 receptor within monocytes. Mutations involving the NALP3 gene cause hereditary periodic fever syndromes in humans. Increased inflammasome activity responsible for uncontrolled IL-1beta production occurs in these syndromes. Inhibition of the IL-1beta pathway by IL-1 receptor antagonist (anakinra) is a highly effective treatment for inherited periodic fever syndromes. A major role for inflammasome activity in the development of gout attacks was established recently. Urate monosodium crystals are specifically detected via the NALP3 inflammasome, which results in marked IL-1beta overproduction and initiation of an inflammatory response. This finding opens up new possibilities for the management of gouty attacks.
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PMID:The inflammasome, autoinflammatory diseases, and gout. 1771 72

The nucleotide-binding domain, leucine-rich repeat containing family (NLR) network has provided pivotal genetic and molecular insights into diseases that were hitherto regarded as autoimmune. The NLR-related disorders include rare monogenic autoinflammatory diseases collectively termed cryopyrin-associated periodic syndromes, Crohn's disease which is a common polygenic disease and also an association at the mechanistic level with gout and pseudogout. Unlike the classical autoimmune diseases where disease immunopathogenesis is played out primarily in the primary and secondary lymphoid organs, the immunopathogenesis of the NLR-related disorders is played out in the tissues where inflammation arises. As the genetic mutations or molecular cascades associated with the NLR-related disorders have a widespread cellular distribution, it has been somewhat enigmatic why these disorders attack certain territories, but not others. This implies that tissue-specific factors in the target organs themselves contribute to disease expression. Such examples include the high abundance of NOD2 expressing cells in the part of the gut most typically afflicted by Crohn's disease and the preferential deposition of crystals in the joints to where inflammation localises in gout and pseudogout. The NLR network is associated principally with increases in TNF or IL-1 production, both of which are key players in innate immunity. Therefore, the NLR network identifies at the genetic and molecular level a robust paradigm for innate immune activation against self. This tissue-specific-factor-associated inflammation is the diametric opposite of classical autoimmunity. Of note, the MHC class-I-associated diseases including psoriasis (HLA-Cw6) and ankylosing spondylitis (HLA-B27) show striking clinical overlaps with Crohn's disease and also some rare monogenic diseases. Thus, the NLR innate immune pathway allows the full spectrum of inflammation against self to be viewed along an immunological disease continuum with autoantibody-associated disease at one end, innate immune diseases at the other and MHC class-1-related disorders as an intermediate.
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PMID:The NLR network and the immunological disease continuum of adaptive and innate immune-mediated inflammation against self. 1780 42

Gout is caused by the deposition of monosodium urate crystals (MSU) in tissue and provokes a local inflammatory reaction. It is the most common form of inflammatory arthritis in the elderly. The formation of MSU crystals is facilitated by hyperuricemia. In the last two decades, both hyperuricemia and gout have increased markedly and similar trends in the epidemiology of the metabolic syndrome have been observed. Recent studies provide new insights into uric acid metabolism in the kidneys as well as possible links between hyperuricemia and hypertension. MSU crystals provoke inflammation by activating leukocytes to produce inflammatory cytokines and other inflammatory mediators. The uptake of MSU crystals by monocytes involves interactions with Toll-like receptors (TLR-2 and TLR-4) and CD14, components of the innate immune system. Intracellularly, MSU crystals activate inflammasomes to activate pro-IL-1 (interleukin 1) processing to yield mature IL-1beta. The inflammatory effects of MSU are IL-1-dependent and can be blocked by IL-1 inhibitors. These advances provide new therapeutic targets to treat hyperuricemia and gout.
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PMID:[New knowledge on the pathophysiology and therapy of gout]. 1792 25

Gout is a disease caused by the deposition of monosodium urate monohydrate (MSU) crystals. Precise mechanisms underlying the initiation of acute gout, however, are not known. Recent investigations provided novel evidence in the pathology of acute gout. A number of studies indicated that MSU crystals can act as a "danger signal" which resembles exogenous adjuvants, and toll-like receptor(TLR)-mediated pathways and/or MyD88-dependent IL-1 receptor pathways are involved in acute gout. Up-regulation of the triggering receptor expressed on myeloid cells 1(TREM-1) in phagocytes by the stimulation with MSU crystals has been demonstrated. Furthermore, pathological significance of NALP 3 inflammasome in gout has been also demonstrated. These findings provide a new insight into the mechanisms underlying the initiation of MSU crystal-induced acute inflammation.
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PMID:[Pathological mechanisms of gouty arthritis]. 1840 19

Gout is the most common form of inflammatory arthritis in the elderly. In the last two decades, both hyperuricemia and gout have increased markedly and similar trends in the epidemiology of the metabolic syndrome have been observed. Recent studies provide new insights into the transporters that handle uric acid in the kidney as well as possible links between these transporters, hyperuricemia, and hypertension. The treatment of established hyperuricemia has also seen new developments. Febuxostat and PEG-uricase are two novel treatments that have been evaluated and shown to be highly effective in the management of hyperuricemia, thus enlarging the therapeutic options available to lower uric acid levels. Monosodium urate (MSU) crystals are potent inducers of inflammation. Within the joint, they trigger a local inflammatory reaction, neutrophil recruitment, and the production of pro-inflammatory cytokines as well as other inflammatory mediators. Experimentally, the uptake of MSU crystals by monocytes involves interactions with components of the innate immune system, namely Toll-like receptor (TLR)-2, TLR-4, and CD14. Intracellularly, MSU crystals activate multiple processes that lead to the formation of the NALP-3 (NACHT, LRR, and pyrin domain-containing-3) inflammasome complex that in turn processes pro-interleukin (IL)-1 to yield mature IL-1 beta, which is then secreted. The inflammatory effects of MSU are IL-1-dependent and can be blocked by IL-1 inhibitors. These advances in the understanding of hyperuricemia and gout provide new therapeutic targets for the future.
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PMID:Developments in the scientific and clinical understanding of gout. 1894 74

The interleukin 1 family is composed by the interleukin 1 (IL-1) and its natural occurring inhibitor, the interleukin 1 receptor antagonist (IL-1Ra). The role of both molecules in rheumatoid arthritis has been widely established, and in this sense new molecules blocking IL-1 actions are under investigation. Anakinra is the recombinant form of IL-1Ra, and has proven to be well tolerated and indicated in the treatment of rheumatoid arthritis. Nevertheless, other molecules such as mAb anti-IL-1 and IL-1 Trap are being developed. Moreover, the recent relation of IL-1 in the inflammasome and pathways of innate immunity has lead to new indications of anti-IL-1 molecules, especially in the autoinflammatory syndromes as well as in other inflammatory diseases. Herein we have performed a review of the literature, limited to English language journals (PUBMED search: combination of descriptors IL-1 and anakinra, systemic juvenile idiopathic arthritis, adult's onset Still's disease, autoinflammatory syndromes, gout, pseudogout, ankylosing spondylitis, and systemic lupus erythematosus from January 1985-December 2008) emphasizing the possible new indications. Although sufficient data is not yet available to fully assess the efficacy and safety of anti-IL-1 molecules in patients with inflammatory disorders other than rheumatoid arthritis, new data is promising.
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PMID:Anti-IL-1 molecules: new comers and new indications. 2004 71

Gout, a disease recognized since antiquity, has increased in prevalence in recent years and the clinical profile of this disease has become increasingly complex, owing to large numbers of cases with iatrogenic factors, multiple comorbidities, advanced age, and hyperuricemia and arthritis refractory to treatment. In this Review, key advances in gout research made during the past decade are summarized. Revised strategies for safe and effective employment of dietary measures and pharmacologic treatments for active gouty arthritis, prevention of gout flares and urate lowering are also reviewed, with an emphasis on dosing of colchicine and allopurinol, and the evidence-based approach to systemic glucocorticosteroid treatment of acute gout. Also discussed are new and emerging treatments for gout and hyperuricemia, and the potential influence of dual energy CT imaging on treatment. In this context, the therapeutic role of febuxostat, and clinical development of pegylated uricase urate-lowering therapy and interleukin 1 antagonism for gouty inflammation are reviewed. Collectively, novel approaches will hopefully lead to improved management of hyperuricemia and gout, and also to improvements in patient-centered outcomes, even for those who have previously failed to respond to treatment.
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PMID:Update on gout: new therapeutic strategies and options. 2004 4

Immune reconstitution inflammatory syndrome (IRIS) describes the initial clinical deterioration some patients manifest upon initiation of effective antiretroviral therapy (ART) for HIV infection. In this report we describe a case of IRIS manifesting as polyarticular gout, a previously unreported rheumatological manifestation of IRIS. A 53-year-old HIV-infected man with a history of intermittent attacks of gout and an initial CD4 count of 112 cells/microL and a viral load of >100,000 copies/mL presented to our institution with severe, refractory, polyarticular gout approximately 4 weeks after initiating ART. At this point, the patient demonstrated significant gains in his CD4 counts (103 cells/microL) and a greater than 3 log decline in his HIV-1- viral load. This episode was prolonged lasting for approximately 10 weeks and required hospitalization for the management of pain and control of inflammation. The temporal associations of this attack with the initiation of ART and the observed immunologic reconstitution make IRIS a clinical possibility.Monosodium urate crystals through their interactions with interleukin 1- beta, and neutrophilic synovitis play a critical role in the pathophysiology of gout. Defects in both neutrophil and macrophage function and imbalances in the cytokine milieu are documented in HIV infected patients. The introduction of ART results in restoration of neutrophil and macrophage function, declines in levels of the anti-inflammatory cytokine IL-10, and increases in levels of proinflammatory cytokines including IL-1 beta, which may provide the necessary milieu for the precipitation of attacks of severe polyarticular gout in the context of ART initiation.
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PMID:Refractory polyarticular gouty arthritis as a manifestation of immune reconstitution inflammatory syndrome. 2005 57

Rilonacept is a dimeric fusion protein consisting of the extracellular domains of interleukin (IL)-1 type 1 receptor and IL-1 receptor accessory protein joined to the constant region (Fc) of human immunoglobulin G1. By incorporating both components of the IL-1 binding complex, rilonacept is able to tightly bind IL-1 with picomolar affinity. Although early clinical results in rheumatoid arthritis (RA) suggested that RA is not primarily an IL-1-driven disease, the discovery that the rare genetic conditions called cryopyrin-associated periodic syndromes (CAPS) were caused by overproduction of IL-1 led to clinical development and approval for these conditions. An assay that detects rilonacept:IL-1 complexes in plasma is helping to identify new indications, such as gout, in which IL-1 overproduction plays a key pathogenic role. The development of rilonacept for CAPS was achieved through collaboration between the pharmaceutical industry, academia, and government agencies, and demonstrates that knowledge gleaned in orphan indications can inform drug development for more common and heterogeneous diseases.
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PMID:Rilonacept--CAPS and beyond. 2007 81


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