Gout: Terkeltaub R

Terkeltaub R. · No affiliation provided · J Rheumatol. · Pubmed #17924606 links to  free full text

This publication has no abstract.

Liu-Bryan R, Terkeltaub R. · No affiliation provided · Arthritis Rheum. · Pubmed #16447213 links to  free full text

This publication has no abstract.

Chao J, Terkeltaub R. · Department of Rheumatology, VA Medical Center, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. · Curr Rheumatol Rep. · Pubmed #19296886 No free full text.

Abstract: Allopurinol, the first-line drug for serum urate-lowering therapy in gout, is approved by the US Food and Drug Administration for a dose up to 800 mg/d and is available as a low-cost generic drug. However, the vast majority of allopurinol prescriptions are for doses < or = 300 mg/d, which often fails to adequately treat hyperuricemia in gout. This situation has been promoted by longstanding, non-evidence-based guidelines for allopurinol use calibrated to renal function (and oxypurinol levels) and designed, without proof of efficacy, to avoid allopurinol hypersensitivity syndrome. Severe allopurinol hypersensitivity reactions are not necessarily dose-dependent and do not always correlate with serum oxypurinol levels. Limiting allopurinol dosing to < or = 300 mg/d suboptimally controls hyperuricemia and fails to adequately prevent hypersensitivity reactions. However, the long-term safety of elevating allopurinol dosages in chronic kidney disease requires further study. The emergence of novel urate-lowering therapeutic options, such as febuxostat and uricase, makes timely this review of current allopurinol dosing guidelines, safety, and efficacy in gout hyperuricemia therapy, including patients with chronic kidney disease.

Terkeltaub R. · VAMC/UCSD, 3350La Jolla Village Drive, 111K, San Diego, California 92161, USA. · Bull NYU Hosp Jt Dis. · Pubmed #17121496 links to  free full text

Abstract: Mechanistic and therapeutic advances in gout have been moving swiftly in the past decade. Clinically, the disease is changing in character. This review discusses several of the pertinent recent developments in understanding gout and in novel therapeutics for the disease. Subjects addressed include the role of URAT1-mediated renal proximal tubule epithelial cell urate anion reabsorption in hyperuricemia. We discuss the therapeutic limitations of allopurinol and uricosurics and the potential applications of novel xanthine oxidase inhibitors and of recombinant uricase preparations. Last, we summarize understanding of the central role of the early induced innate immune response in gouty inflammation, which has suggested the potential value of new strategies for treating gouty inflammation by targeting caspase-1 or IL-1beta.

Terkeltaub R, Bushinsky DA, Becker MA. · San Diego VAMC Rheumatology Section, and University of California San Diego, La Jolla, California, USA. · Arthritis Res Ther. · Pubmed #16820043 No free full text.

Abstract: Although dietary, genetic, or disease-related excesses in urate production may contribute to hyperuricemia, impaired renal excretion of uric acid is the dominant cause of hyperuricemia in the majority of patients with gout. The aims of this review are to highlight exciting and clinically pertinent advances in our understanding of how uric acid is reabsorbed by the kidney under the regulation of urate transporter (URAT)1 and other recently identified urate transporters; to discuss urate-lowering agents in clinical development; and to summarize the limitations of currently available antihyperuricemic drugs. The use of uricosuric drugs to treat hyperuricemia in patients with gout is limited by prior urolothiasis or renal dysfunction. For this reason, our discussion focuses on the development of the novel xanthine oxidase inhibitor febuxostat and modified recombinant uricase preparations.

Cronstein BN, Terkeltaub R. · Department of Medicine and Division of Clinical Pharmacology, New York University School of Medicine, New York, New York, USA. · Arthritis Res Ther. · Pubmed #16820042 No free full text.

Abstract: Gouty arthritis is a characteristically intense acute inflammatory reaction that erupts in response to articular deposits of monosodium urate (MSU) crystals. Important recent molecular biologic advances in this field have given us a clear picture of the mechanistic basis of gouty inflammation. The innate immune inflammatory response is critically involved in the pathology of gout. Specifically, MSU crystals promote inflammation directly by stimulating cells via Toll-like receptor signaling and by providing a surface for cleavage of C5 and formation of complement membrane attack complex (C5b-9), culminating in secretion of cytokines, chemokines, and other inflammatory mediators with a dramatic influx of neutrophils into the joint. Despite the detailed mechanistic picture for gouty inflammation, there are no placebo-controlled, randomized clinical studies for any of the therapies commonly used, although comparative studies have demonstrated that many nonsteroidal anti-inflammatory drugs are equivalent to indomethacin with respect to controlling acute gouty attacks. In general, the first line of anti-inflammatory therapy for acute gout is nonsteroidal anti-inflammatory drugs, and the selective cyclo-oxygenase-2 inhibitor celecoxib can be used where appropriate. The second line of treatment is glucocorticosteroids, given systemically (oral, intravenous, or intramuscular) or intra-articularly. Alternatively, synthetic adrenocorticotropic hormone is effective, partly via induction of adrenal glucocorticosteroids and partly via rapid peripheral suppression of leukocyte activation by melatonin receptor 3 signaling. The third line of treatment is oral colchicine, which is highly effective when given early in an acute gouty attack, but it is poorly tolerated because of predictable gastrointestinal side effects.

Wu CW, Terkeltaub R, Kalunian KC. · University of California San Diego, Division of Rheumatology and Allergy-Immunology, 9320 Campus Point Drive #227, La Jolla, CA 92037, USA. . · Curr Rheumatol Rep. · Pubmed #15918998 No free full text.

Abstract: The clinical implication of articular deposits of calcium-containing crystals (specifically of calcium pyrophosphate dihydrate and hydroxyapatite) in osteoarthritis is unknown. Recent longitudinal studies have suggested that in some instances calcium crystals are direct participants in cartilage damage, while in other situations they are merely markers of joint damage. Better understanding of the mechanisms of crystal formation, especially in relation to inorganic pyrophosphate regulation, has lead to potential avenues for therapeutic intervention. The current treatment of osteoarthritis associated with calcium-containing crystals should involve nonsteroidal anti-inflammatory drugs, intra-articular steroids, and in resistant cases, joint irrigation can be considered. While preliminary studies suggest the possibility of favorable benefits from colchicine and hydroxycholorquine in this osteoarthritis disease subset, more rigorous studies need to be conducted to establish their roles.

Terkeltaub R, Zelman D, Scavulli J, Perez-Ruiz F, Lioté F. · Veterans Affairs Medical Center, University of California San Diego, 111K, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. · Joint Bone Spine. · Pubmed #19559637 No free full text.

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Lee SJ, Hirsch JD, Terkeltaub R, Khanna D, Singh JA, Sarkin A, Kavanaugh A. · San Diego Veterans Affairs Medical Center, San Diego, CA, USA. · Rheumatology (Oxford). · Pubmed #19307257 No free full text.

Abstract: OBJECTIVE: To assess the impact of gout on health-related quality of life (HRQoL) among patients in three large US cities. METHODS: Gout patients completed the Short Form-36 (SF-36) and a series of questions regarding their gout, comorbidities and demographics. Their physicians confirmed the gout diagnosis and evaluated the severity of patient's gout. The differences in mean norm-based SF-36 scores between the US norms and gout patients and between subgroups of gout patients were calculated. The relative weight and significance of gout-related characteristics associated with patients' HRQoL were also calculated. RESULTS: The majority of the patients were males with a mean age of 62.2 years and median disease duration of 13.8 years. Most were overweight/obese with several comorbidities. Half of the patients experienced three or more gout attacks per year with a typical gout attack involving five joints and lasting for at least 4 days. The Physical Component Summary (PCS) and Mental Component Summary (MCS) was significantly lower for gout patients (P < 0.002 and P < 0.001, respectively). Among gout patients, the mean PCS and MCS were lower for those with more frequent gout attacks and greater number of affected joints (P < 0.005 and P < 0.001, respectively). After adjusting for age, gender and comorbidities, the number of joints involved during a typical and the worst gout attack had the greatest impact on patient's PCS and MCS. CONCLUSION: Gout patients had clinically significant lower HRQoL than their age-matched US norm. Comorbidities and several additional gout-related factors significantly impacted the overall HRQoL.

Hirsch JD, Lee SJ, Terkeltaub R, Khanna D, Singh J, Sarkin A, Harvey J, Kavanaugh A. · Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093-0714, USA. · J Rheumatol. · Pubmed #18925685 No free full text.

Abstract: OBJECTIVE: To evaluate the reliability and validity of an instrument assessing the influence of gout (acute and chronic) on health-related quality of life (HRQOL). METHODS: Focus groups were used to examine the content of an existing Gout Assessment Questionnaire (GAQ1.0). GAQ2.0 was developed, consisting of a section describing the impact of gout on HRQOL [Gout Impact (GI)] and 4 sections describing subjects' gout overall and demographic data. The GAQ2.0 and the Medical Outcomes Study Short Form-36 Version 2 (SF-36v2) were completed by gout patients in 3 US cities. GI scales were examined using clinical judgment, review of item statistics, Rasch analysis, and confirmatory factor analysis. RESULTS: Subjects (n = 308) were predominantly male (90.2%), Caucasian (75.9%), with a mean age 62.2 +/- 11.8 years. Half the subjects (49.7%) reported > or = 3 attacks in the past year. Two-week test-retest reliability for each scale was good (0.77 to 0.89) for all 5 GI scales. All scales achieved high sufficient (0.86 to 0.89) or excellent (0.93 to 0.97) ratings based on 10-item adjusted alpha coefficients. Correlations and tests among known groups indicated subjects with more severe gout had higher GI scores (i.e., greater gout impact). GI scores correlated more highly with patient-reported measures of gout severity than the SF-36v2 and several traditional measures of gout severity. CONCLUSION: The GAQ2.0 is an instrument for measuring the impact of gout on HRQOL. The GI section exhibited acceptable reliability and validity characteristics. Future studies should assess GI responsiveness, minimally important differences, and psychometric properties in other patient populations.

Hennigan S, Terkeltaub R. · Rheumatology-Allergy-Immunology Division, University of California School of Medicine, VA Medical Center, San Diego, CA 92161, USA. · Curr Rheumatol Rep. · Pubmed #17531176 No free full text.

This publication has no abstract.

Scott P, Ma H, Viriyakosol S, Terkeltaub R, Liu-Bryan R. · Veterans Affairs Medical Center, Department of Medicine, University of California-San Diego, San Diego, CA 92161, USA. · J Immunol. · Pubmed #17056568 links to  free full text

Abstract: Phagocyte ingestion of monosodium urate (MSU) crystals can induce proinflammatory responses and trigger acute gouty inflammation. Alternatively, the uptake of MSU crystals by mature macrophages can be noninflammatory and promote resolution of gouty inflammation. Macrophage activation by extracellular MSU crystals involves apparent recognition and ingestion mediated by TLR2 and TLR4, with subsequent intracellular recognition linked to caspase-1 activation and IL-1beta processing driven by the NACHT-LRR-PYD-containing protein-3 inflammasome. In this study, we examined the potential role in gouty inflammation of CD14, a phagocyte-expressed pattern recognition receptor that functionally interacts with both TLR2 and TLR4. MSU crystals, but not latex beads, directly bound recombinant soluble (s) CD14 in vitro. CD14(-/-) bone marrow-derived macrophages (BMDMs) demonstrated unimpaired phagocytosis of MSU crystals but reduced p38 phosphorylation and approximately 90% less IL-1beta and CXCL1 release. Attenuated MSU crystal-induced IL-1beta release in CD14(-/-) BMDMs was mediated by decreased pro-IL-1beta protein expression and additionally by decreased caspase-1 activation and IL-1beta processing consistent with diminished NACHT-LRR-PYD-containing protein-3 inflammasome activation. Coating of MSU crystals with sCD14, but not sTLR2 or sTLR4, restored IL-1beta and CXCL1 production in CD14(-/-) BMDMs in vitro. Gain of function of CD14 directly enhanced TLR4-mediated signaling in response to MSU crystals in transfected Chinese hamster ovary cells in vitro. Last, MSU crystal-induced leukocyte influx at 6 h was reduced by approximately 75%, and local induction of IL-1beta decreased by >80% in CD14(-/-) mouse s.c. air pouches in vivo. We conclude that engagement of CD14 is a central determinant of the inflammatory potential of MSU crystals.

Rose DM, Sydlaske AD, Agha-Babakhani A, Johnson K, Terkeltaub R. · VA Medical Center, University of California, San Diego, CA 92161, USA. · Arthritis Rheum. · Pubmed #17009310 links to  free full text

Abstract: OBJECTIVE: Monosodium urate monohydrate (MSU) crystals have remarkable inflammatory potential. However, gouty inflammation is spontaneously self-limited, an occurrence recognized since antiquity. Gouty synovitis is driven and sustained by neutrophil influx. Importantly, macrophage phagocytosis of apoptotic (but not necrotic) neutrophils is antiinflammatory. Therefore, we tested the hypothesis that efficient clearance of apoptotic neutrophils by macrophages is one of the factors that restrains the progression of gouty inflammation. Macrophage expression of transglutaminase 2 (TG2), a multifunctional protein with reciprocally regulated transamidation and purine nucleotide-binding activities, promotes apoptotic leukocyte uptake. In this study, we tested the specific role of macrophage TG2 expression in MSU crystal-induced inflammation. METHODS: We studied MSU crystal-induced peritonitis in TG2-/- and congenic TG2+/+ mice. We also studied the effects of TG2 on apoptotic cell uptake by cultured macrophages. RESULTS: TG2-/- mice demonstrated more progressive neutrophilic accumulation than did TG2+/+ mice, which was associated with delayed clearance of apoptotic neutrophils during MSU crystal-induced peritonitis. We observed defective phagocytosis of apoptotic leukocytes by TG2-/- peritoneal macrophages, which was corrected by soluble extracellular TG2. Transamidation catalytic activity of TG2 was not required to mediate macrophage uptake of apoptotic leukocytes. In contrast, the TG2 nucleotide binding site residue K173 was critical for this TG2 function. TG2 bound to GDP, ADP, or ATP (but not to GTP) rescued defective apoptotic leukocyte uptake by TG2-/- macrophages. CONCLUSION: Enhancement of apoptotic neutrophil uptake by macrophage-derived TG2 restrains gout-like neutrophilic peritoneal inflammation. Differential binding of TG2 by purine nucleotides may contribute to clinical variability in the extent and duration of gouty inflammation.

Liu-Bryan R, Scott P, Sydlaske A, Rose DM, Terkeltaub R. · VA Medical Center, University of California, San Diego 92161, USA. · Arthritis Rheum. · Pubmed #16142712 links to  free full text

Abstract: OBJECTIVE: In gout, incompletely defined molecular factors alter recognition of dormant articular and bursal monosodium urate monohydrate (MSU) crystal deposits, thereby inducing self-limiting bouts of characteristically severe neutrophilic inflammation. To define primary determinants of cellular recognition, uptake, and inflammatory responses to MSU crystals, we conducted a study to test the role of Toll-like receptor 2 (TLR-2), TLR-4, and the cytosolic TLR adapter protein myeloid differentiation factor 88 (MyD88), which are centrally involved in innate immune recognition of microbial pathogens. METHODS: We isolated bone marrow-derived macrophages (BMDMs) in TLR-2-/-, TLR-4-/-, MyD88-/-, and congenic wild-type mice, and assessed phagocytosis and cytokine expression in response to endotoxin-free MSU crystals under serum-free conditions. MSU crystals also were injected into mouse synovium-like subcutaneous air pouches. RESULTS: TLR-2-/-, TLR-4-/-, and MyD88-/- BMDMs demonstrated impaired uptake of MSU crystals in vitro. MSU crystal-induced production of interleukin-1beta (IL-1beta), tumor necrosis factor alpha, keratinocyte-derived cytokine/growth-related oncogene alpha, and transforming growth factor beta1 also were significantly suppressed in TLR-2-/- and TLR-4-/- BMDMs and were blunted in MyD88-/- BMDMs in vitro. Neutrophil influx and local induction of IL-1beta in subcutaneous air pouches were suppressed 6 hours after injection of MSU crystals in TLR-2-/- and TLR-4-/- mice and were attenuated in MyD88-/- mice. CONCLUSION: The murine host requires TLR-2, TLR-4, and MyD88 for macrophage activation and development of full-blown neutrophilic, air pouch inflammation in response to MSU crystals. Our findings implicate innate immune cellular recognition of naked MSU crystals by specific TLRs as a major factor in determining the inflammatory potential of MSU crystal deposits and the course of gouty arthritis.

Liu-Bryan R, Pritzker K, Firestein GS, Terkeltaub R. · Veterans Affairs Medical Center, San Diego, CA 92161, USA. · J Immunol. · Pubmed #15814732 links to  free full text

Abstract: Microcrystals of calcium pyrophosphate dihydrate (CPPD) and monosodium urate (MSU) deposited in synovium and articular cartilage initiate joint inflammation and cartilage degradation in large part by binding and directly activating resident cells. TLRs trigger innate host defense responses to infectious pathogens, and the expression of certain TLRs by synovial fibroblasts has revealed the potential for innate immune responses to be triggered by mesenchymally derived resident cells in the joint. In this study we tested the hypothesis that chondrocytes also express TLRs and that one or more TLRs centrally mediate chondrocyte responsiveness to CPPD and MSU crystals in vitro. We detected TLR2 expression in normal articular chondrocytes and up-regulation of TLR2 in osteoarthritic cartilage chondrocytes in situ. We demonstrated that transient transfection of TLR2 signaling-negative regulator Toll-interacting protein or treatment with TLR2-blocking Ab suppressed CPPD and MSU crystal-induced chondrocyte release of NO, an inflammatory mediator that promotes cartilage degeneration. Conversely, gain-of-function of TLR2 in normal chondrocytes via transfection was associated with increased CPPD and MSU crystal-induced NO release. Canonical TLR signaling by parallel pathways involving MyD88, IL-1R-associated kinase 1, TNF receptor-associated factor 6, and IkappaB kinase and Rac1, PI3K, and Akt critically mediated NO release in chondrocytes stimulated by both CPPD and MSU crystals. We conclude that CPPD and MSU crystals critically use TLR2-mediated signaling in chondrocytes to trigger NO generation. Our results indicate the potential for innate immunity at the level of the articular chondrocyte to directly contribute to inflammatory and degenerative tissue reactions associated with both gout and pseudogout.

Liu R, Lioté F, Rose DM, Merz D, Terkeltaub R. · VA Medical Center and University of California, San Diego, CA 92161, USA. · Arthritis Rheum. · Pubmed #14730623 links to  free full text

Abstract: OBJECTIVE: Articular deposition of monosodium urate monohydrate (MSU) crystals may promote cartilage and bone erosion. Therefore, the aim of this study was to determine how MSU crystals stimulate chondrocytes. METHODS: Nitric oxide (NO) release, and expression of inducible nitric oxide synthase (iNOS) and matrix metalloproteinase 3 (MMP-3) were assessed in cultured chondrocytes treated with MSU. MSU-induced functional signaling by specific protein kinases (p38, Src, and the focal adhesion kinase [FAK] family members proline-rich tyrosine kinase 2 [Pyk-2] and FAK) was also examined using selective pharmacologic inhibitors and transfection of kinase mutants. RESULTS: MSU induced MMP-3 and iNOS expression and NO release in chondrocytes in a p38-dependent manner that did not require interleukin-1 (IL-1), as demonstrated by using IL-1 receptor antagonist. MSU induced rapid tyrosine phosphorylation of Pyk-2 and FAK, their adaptor protein paxillin, and interacting kinase c-Src. Pyk-2 and c-Src signaling both mediated p38 MAPK activation in response to MSU. Pyk-2 and c-Src signaling played a major role in transducing MSU-induced NO production and MMP-3 expression. But, despite the observed FAK phosphorylation, a selective pharmacologic FAK inhibitor and a FAK dominant-negative mutant both failed to block MSU-induced NO release or MMP-3 expression in parallel experiments. CONCLUSION: In chondrocytes, MSU crystals activate a signaling kinase cascade typically employed by adhesion receptors that involves upstream Src and FAK family activation and downstream p38 activation. In this cascade, Pyk-2, Src, and p38 kinases transduce MSU-induced NO production and MMP-3 expression. Our results identify Pyk-2 and c-Src as novel sites for potential therapeutic intervention in cartilage degradation in chronic gout.

Liu R, Aupperle K, Terkeltaub R. · Veterans Affairs Medical Center and Rheumatology-Allergy/Immunology Division, Department of Medicine, University of California, San Diego 92161, USA. · J Leukoc Biol. · Pubmed #11739559 links to  free full text

Abstract: Neutrophil-dependent inflammation dependent on monosodium urate (MSU) crystal-induced IL-8 expression occurs in gout. MSU crystals activate phagocyte Src family tyrosine kinases and the serine/threonine kinase p70s6k. Thus, using monocytic THP-1 cells, we assessed the potential for Src family kinases and p70s6k to mediate MSU-induced IL-8 expression. MSU crystals induced phosphorylation of p70s6k and the Src kinases c-Src, Lyn, Hck, and Fyn. IL-8 expression was attenuated more by the Src kinase inhibitor PP1 than by the p70s6k inhibitor rapamycin. PP1 inhibited crystal-induced phosphorylation of ERK1/2 and IkappaBalpha and suppressed IkappaB kinase (IKK) activation and NF-kappaB binding to the IL-8 promoter, signals that mediate MSU-induced IL-8 expression. Transfection of the native Src inhibitor, C-terminal Src kinase (Csk), also suppressed crystal-induced c-Src, ERK1/2, and IkappaBalpha phosphorylation and IL-8 expression. We conclude that Src family tyrosine kinase signaling plays a significant role in MSU crystal-induced IL-8 expression via stimulation of ERK1/2 pathway and NF-kappaB activation.

Terkeltaub R. · No affiliation provided · Curr Rheumatol Rep. · Pubmed #11177765 No free full text.

This publication has no abstract.

Liu R, O'Connell M, Johnson K, Pritzker K, Mackman N, Terkeltaub R. · Department of Veterans Affairs Medical Center, University of California, San Diego 92161, USA. · Arthritis Rheum. · Pubmed #10817569 links to  free full text

Abstract: OBJECTIVE: Monosodium urate monohydrate (MSU) and calcium pyrophosphate dihydrate (CPPD) crystals cause acute gout and pseudogout, respectively. Because acute gout and pseudogout appear to be dependent on interleukin-8 (IL-8)-induced neutrophil ingress, this study was undertaken to define and compare how MSU and CPPD crystals stimulate IL-8 messenger RNA (mRNA) expression in mononuclear phagocytes. METHODS: MSU and CPPD crystal-induced mitogen-activated protein kinase (MAPK) signal transduction and IL-8 transcriptional activation were studied in human monocytic cells, using the THP-1 cell line. RESULTS: MSU and CPPD crystals (0.5 mg/ml) induced activation of c-Jun N-terminal kinase, extracellular signal-regulated kinase 1 (ERK-1)/ERK-2, and p38 MAPK pathways in THP-1 cells. Activation of the ERK-1/ERK-2 pathway was essential for MSU and CPPD crystal-induced IL-8 mRNA expression, whereas the p38 pathway played a greater role in IL-8 mRNA expression in response to CPPD crystals in comparison with MSU crystals. Both crystals induced the binding of nuclear factor kappaB (NF-kappaB), including the NF-kappaB complex c-Rel/RelA, and activator protein 1 (AP-1, including N-terminal phosphorylated c-Jun) to the IL-8 promoter. Both crystals induced transcriptional activation of the IL-8 promoter, which was dependent on activation of c-Rel/RelA and AP-1. Activation of the NF-IL-6 transcription factor played a lesser role. Finally, crystal-induced IL-8 promoter activation was mediated by activation of the ERK-1/ERK-2 pathway, as demonstrated by transfection of dominant-negative raf-1. CONCLUSION: These results indicate that ERK-1/ ERK-2 signaling and transcriptional activation through AP-1 and NF-kappaB are essential for the induction of IL-8 expression in mononuclear phagocytes in response to CPPD and MSU crystals.