Gota: Avances Diagnosticos, Terapéuticos y Rol de los Biológicos

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Por: Dr. Andy Abril (USA)

XIII Congreso Colombiano de Reumatologia 2011 Barranquilla

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  • Arromdee et al studied the Rochester Epidemiology Project computerized medical record system and found that the incidence of gout has increased over 2 decades. From 1977-1978, 18 cases of primary gout were newly diagnosed versus the 60 new cases between 1995-1996. When adjusting the annual incidence rate for age and sex, it was found that the rate of primary gout had significantly increased (greater than 2-fold) over the past 20 years ( P <.001). The age-adjusted annual incidence for all gout increased from 45/100,000 to 62.3/100,000. The incidence of secondary gout did not change. This information is graphically depicted on the slide according to the age at diagnosis Arromdee et al. J Rheumatol . 2002;29:2403-2406.
  • Gout is the most common inflammatory joint disease in men over 40 years of age 1 and, according to NHANES III data, is thought to have affected more than 5 million Americans between 1988 and 1994. 2 This figure for gout may be even greater today, as a study by Wallace and colleagues demonstrated that the number of cases increased from 2.9 per 1000 in 1990 to 5.2 per 1000 in 1999. 3 This information is graphically depicted on the slide. 1. Roubenoff et al. Rheum Dis Clin North Am . 1990;16:539-550. 2. Kramer. Am J Kidney Disease. 2002;40:37-42. 3. Wallace et al. J Rheum. 2004;31:1582-1587.
  • The National Health and Nutrition Examination Survey (NHANES) is a program of studies designed to assess the health and nutritional status of adults and children in the United States. The survey is unique in that it combines interviews and physical examinations 1. Roubenoff et al. Rheum Dis Clin North Am . 1990;16:539-550. 2. Kramer. Am J Kidney Disease. 2002;40:37-42. 3. Wallace et al. J Rheum. 2004;31:1582-1587.
  • Gout is the most common inflammatory joint disease in men over 40 years of age 1 and, according to NHANES III data, is thought to have affected more than 5 million Americans between 1988 and 1994. 2 This figure for gout may be even greater today, as a study by Wallace and colleagues demonstrated that the number of cases increased from 2.9 per 1000 in 1990 to 5.2 per 1000 in 1999. 3 This information is graphically depicted on the slide. 1. Roubenoff et al. Rheum Dis Clin North Am . 1990;16:539-550. 2. Kramer. Am J Kidney Disease. 2002;40:37-42. 3. Wallace et al. J Rheum. 2004;31:1582-1587.
  • The increasing prevalence of hyperuricemia is clearly a contributor to the increase in gout. Results from studies performed in 1960, 1 1967, 2 1991, 3 and 2003 4 suggest that an increasing number of people fit the definition for hyperuricemia (serum urate ≥ 6.8 mg/dL). Although this information was not obtained by a single, long-term follow-up study, it does strongly support the view that serum urate levels are increasing in the general population. 1. Mikkelsen et al. Am J Med. 1965;39:242-251. 2. Hall et al. Am J Med. 1967;42:27-37. 3. Lin et al. J Rheumatol. 2000;27:1045-1050. 4. Yu K-H et al. Rheumatology . 2004;43:1541-1545.
  • There is now an increasing number of studies showing at a population level some associations with hyperuricemia and cardiovascular outcomes, including cardiovascular mortality. Most of these studies have been done in the last 5 years, so this is a newer area of investigation that still requires further studies. These studies may help to determine if lowering uric acid decreases cardiovascular morbidity and mortality, an area that is still in question.
  • - The observation that hyperuricemia precedes the development of hypertension indicates that it is not simply a result of hypertension per se. Hyperuricemia is also more common in primary hypertension than in secondary hypertension, at least in adolescents - The observation that uric acid levels were not elevated in secondary hypertension also reduces the likelihood that the hyperuricemia results from hypertension.
  • Figure 1. Proposed Mechanism for Uric Acid–Mediated Hypertension. Excessive intake of fructose or purine-rich meats or exposure to low doses of lead may result in chronic hyperuricemia. Mothers with high uric acid levels that are the result of diet or conditions such as preexisting hypertension, obesity, or preeclampsia may transfer uric acid into the fetal circulation through the placenta, which may ultimately contribute to intrauterine growth retardation (IUGR) and a reduction in nephron number. Among babies born with a low nephron number, hyperuricemia may develop in childhood because of genetic or environmental factors. Chronic hyperuricemia would stimulate the renin–angiotensin system and inhibit release of endothelial nitric oxide, contributing to renal vasoconstriction and possibly increasing blood pressure. Persistent renal vasoconstriction may contribute to arteriolosclerosis and the development of salt-sensitive hypertension, even if the hyperuricemia is corrected. ROS denotes reactive oxygen species.
  • 11. MSU Crystals, compensated polarized light ASF-37 Upjohn
  • 1- Puig JG, de Miguel E, Castillo MC, Rocha AL, Martinez MA,Torres RJ: Asymptomatic hyperuricemia: impact of ultrasonography. Nucleosides Nucleotides Nucleic Acids 2008, 27: 592-595. Small tophaceous deposits were found in 12 (34%) of these patients, and an increased power-Doppler signal was observed in eight (23%) patients, suggesting onsite inflammation. 2- Wright SA. Filippucci E. McVeigh C. Grey A. McCarron M. Grassi W. Wright GD. Taggart AJ: High-resolution ultrasonography of the first metatarsal phalangeal joint in gout: a controlled study. Ann Rheum Dis 2007, 66: 859-864. Comparison of high-resolution US with conventional X-ray imaging in the metatarsal phalangeal joints of gouty patients found changes suggesting gout in 22 metatarsal phalangeal joints in patients with gout who had never been subjected to an attack of acute gout [29]. Erosions were detected three times more frequently by high-resolution US than on X-ray imaging. 3-Rettenbacher T,Ennemoser S,Weirich H, Ulmer H, Hartig F, Klotz W, Herold M: Diagnostic imaging of gout: comparison of highresolution US versus conventional X-ray. Eur J Radiol 2008, 18: 621-630. Another study comparing high-resolution US with conventional radiography, the authors found conventional radiography to have a sensitivity of 31% (32/102) and a specificity of 93% (55/59) in showing features of gout, versus US that had a sensitivity of 96% (98/102) and a specificity of 73% (43/59) in showing features of gout
  • Figure 1. High-resolution ultrasound (HRUS) representation of erosions in metatarsophalangeal joints (MTPJs) of patients with gout. (A) Longitudinal and (B) transverse HRUS of right 1st MTPJ showing a focal bone erosion on the metatarsal head. (C) Longitudinal HRUS of left 1st MTPJ showing multifocal erosions on the metatarsal head. (D) Transverse HRUS with power Doppler of right 1st MTPJ showing two erosions on the metatarsal head, one with power Doppler signal (hot erosion) and the other with no power Doppler signal (cold erosion). M, metatarsal; P, phalanx; white arrow, erosion.
  • Figure 2. High-resolution ultrasound (HRUS) representation of soft tophus-like lesions in metatarsophalangeal joints (MTPJs) of patients with gout. (A) Longitudinal HRUS of left 1st MTPJ showing a large soft tophus-like lesion with evidence of the double contour sign, and (B) marked power Doppler signal in the soft tophus-like lesion. (C) Longitudinal HRUS of right 1st MTPJ showing two separate soft tophi-like lesions in the joint. M, metatarsal; P, phalanx; white arrow, double contour sign; broken white line, margin of soft tophus-like lesion.
  • Figure 3. High-resolution ultrasound (HRUS) representation of hard tophus-like lesions in metatarsophalangeal joints (MTPJ) of patients with gout. Longitudinal HRUS of right 1st MTPJ showing hard tophus-like lesion on extensor tendon, joint effusion, synovial hypertrophy and the double contour sign. M, metatarsal; P, phalanx; white arrow, hard tophus-like lesion; Et, extensor tendon; *, double contour sign; #, joint effusion; white triangle, synovial hypertrophy.
  • Ultrasonography patterns indicating the presence of gout . (a) Double contour sign: transversal ultrasound imaging of the knee joint in the anterior intercondile area. The double contour image is shown as an anechoic line paralleling bony contour femoral cartilage. B-mode, linear transducers with a frequency of 9 MHz. C, knee condyles. (b) Hyperechoic images: longitudinal ultrasound imaging of the dorsal aspect of the first metatarsal phalangeal joint. The hyperechoic cloudy area represents monosodium urate deposits within the thickened synovial membrane (arrows). B-mode, linear transducers with a frequency of 9 MHz. MH, metatarsal head. (c) Power-Doppler signal: longitudinal view, dorsal aspect of an asymptomatic first metatarsal phalangeal joints. The Doppler signal may be seen even seen in hyperechoic synovial areas. Transducer with a frequency of 14 MHz in grey scale and colour Doppler with a frequency of 7.5 MHz.
  • A dual energy computed tomography (DECT) scan is a computerized X-Ray with two X-Ray beams (instead of one beam standardly used in regular CT scans). This tool can be used to produce 3-D images that use color coding to differentiate between different materials in the body. Each of the two beams is set to a different "energy" (like a wave frequency). The idea is that different materials in the body (such as calcium , uric acid, soft tissue, etc) all absorb radiation to varying degrees at the two frequencies. Thus, depending on the degree of radiation absorbed by a particular tissue, the scanner can identify what the tissue is comprised of. The computer can then code different tissues with different colors, so that it is easy to see what a region is comprised of at a glance
  • The two-material decomposition algorithm is based on the physical principle that attenuation of photons depends on atomic number and energy of the photons. Material with a high atomic number (e.g., calcium) has a higher change in attenuation than does material with low-atomic number components (e.g., uric acid). This differencein attenuation directly translates into a difference in CT values. Fig. 2— Syngo Dual Energy software (Siemens Healthcare). Screen shot of gout algorithm shows differences in attenuation between trabecular bone, uric acid, and cortical bone: y -axis represents attenuation values of lower kilovoltage tube (80 kV), and x -axis represents attenuation values of higher kilovoltage tube (140 kV). Compounds above line represent calcium, and compounds below line represent uric acid.
  • Figure 4. Present understanding of uric acid reabsorption and effects of uricosuric drugs in the proximal renal tubule Filtered uric acid is exchanged for monocarboxylates through URAT1 and dicarboxylates through OAT4 on the apical side of the tubule cell. SLC2A9v2 (GLUT9ΔN) also transports uric acid into the cell, then SLC2A9v1 (GLUT9) transports it out of the cell through the basolateral membrane and back into the circulation, along with glucose and fructose. OAT1 and OAT3 are involved in the movement of uric acid through the basolateral membrane, although details are unclear. RDEA594 seems to be distinct from traditional uricosuric drugs in that it inhibits only URAT1 and not the basolateral transporters. The sodium-dependent monocarboxylate transporters SLC5A8 and SLC5A12 and dicarboxlyate transporter SLC13A3 are also shown. Transporters involved in uric acid secretion into the tubule are not shown. See text for references. Modified from reference 60 with permission of authors and publisher (Oxford University Press©).
  • FIGURE 1. The production of uric acid via the purine catabolic pathway. In humans, this pathway ends at uric acid, while the majority of mammals have uricase, which further metabolizes uric acid to a more soluble end-product allantoin. Xanthine oxidase inhibitors (allopurinol and febuxostat) block the conversion of hypoxanthine to xanthine and xanthine to uric acid. The administration of recombinant uricases (rasburicase and pegloticase) is currently being explored as ULT in patients refractory to other agents. www.americantherapeutics.
  • Serum urate also can be lowered by inhibiting production. This is done by blocking the actions of the enzyme xanthine oxidase, responsible for the final steps in the conversions of purines to serum urate. Allopurinol is currently the only approved xanthine oxidase inhibitor. Allopurinol and its active metabolite oxypurinol are both purine analogs, which is evident by the close resemblance in structure to the purine bases hypoxanthine and xanthine. By blocking the production of serum urate, allopurinol and oxypurinol cause the accumulation of the precursors hypoxanthine and xanthine. These precursors are much more soluble than serum urate, so the chances of crystallization and precipitation of these bases are much lower. This significantly decreases the likelihood of the clinical manifestations of gout.
  • An agent currently in phase III studies for the treatment of hyperuricemia associated with gout is febuxostat. Febuxostat is a nonpurine selective inhibitor of xanthine oxidase. Unlike allopurinol, the nonpurine structure of febuxostat does not inhibit any other enzymes in the purine and pyrimidine pathways, so it is selective specifically for the enzyme xanthine oxidase. 1 Furthermore, febuxostat is mainly metabolized by the liver, so it is able to be administered in renal insufficiency 2 with no dosage adjustments. Studies have also demonstrated that dosage adjustments are not necessary when administering febuxostat to patients with mild or moderate hepatic insufficiency. 3 Febuxostat was also found to be safe, effective and well-tolerated over 2 years or longer in patients with a history of allopurinol-intolerance, or a history of a reaction to allopurinol precluding rechallenge. 4 1. Zhao et al. Arthritis Rheum . 2003;48(9):S531. 2. Swan et al. Arthritis Rheum. 2003;48(9):S529. 3. Khosravan et al. Arthritis Rheum. 2004;50(9):S806. 4. Becker et al. Arthritis Rheum. 2004;50(9):S803.
  • Figure 2. Subjects Requiring Treatment for Gout Flares. The percentage of subjects in each interval is calculated by dividing the number of subjects with at least one gout flare in that interval by the number of subjects exposed to at least one dose of drug in that interval. Subjects may be counted in more than one interval. The subjects received prophylaxis during the period from day 1 to week 8. The results for the 80-mg febuxostat group are shown in blue, those for the 120-mg febuxostat group in pink, and those for the allopurinol group in yellow
  • Objetivos primarios
  • FIGURE 1. The production of uric acid via the purine catabolic pathway. In humans, this pathway ends at uric acid, while the majority of mammals have uricase, which further metabolizes uric acid to a more soluble end-product allantoin. Xanthine oxidase inhibitors (allopurinol and febuxostat) block the conversion of hypoxanthine to xanthine and xanthine to uric acid. The administration of recombinant uricases (rasburicase and pegloticase) is currently being explored as ULT in patients refractory to other agents. www.americantherapeutics.
  • FIGURE 1. The production of uric acid via the purine catabolic pathway. In humans, this pathway ends at uric acid, while the majority of mammals have uricase, which further metabolizes uric acid to a more soluble end-product allantoin. Xanthine oxidase inhibitors (allopurinol and febuxostat) block the conversion of hypoxanthine to xanthine and xanthine to uric acid. The administration of recombinant uricases (rasburicase and pegloticase) is currently being explored as ULT in patients refractory to other agents. www.americantherapeutics.
  • Rasburicase is a uricase enzyme preparation that is currently available in the United States for control of hyperuricemia associated with tumor lysis syndrome. This is a potentially life-threatening syndrome that is associated with treatment-related destruction of tumors. The resultant hyperuricemia can lead to renal failure. Clinical studies have shown that rasburicase is effective at lowering serum urate in this condition, 1 but its usefulness in gout has yet to be determined. There is hope that the PEGylated agents currently in development will reduce the antigenicity, and subsequent life-threatening complications, associated with rasburicase. 2 Highly antigenic and short half life 1. Coiffier et al. J Clin Oncol . 2003;21:4402-4406. 2. Elitek Package Insert. Sanofi-Synthelabo Inc. 2001.
  • All uricase therapies have the potential to induce oxidative stress, since degradation of the high micromolar plasma concentrations of urate in gout patients by uricases has the capacity to generate substantial amounts of hydrogen peroxide glucose-6-phosphate dehydrogenase deficiency in some but not all affected subjects [59,60]; subsequently, this deficiency has become an exclusion criterion for any uricase therapy
  • Study population. Patients were enrolled at 9 academic and private-practice rheumatology sites in the US during 2004. Patients studied were hyperuricemic (serum urate 8 mg/dl at screening) adult men and women (age 18 years) with established and symptomatic gout, defined as the presence of at least 1 of the following: 1 tophus, 1 gout flare within the previous 6 months, or chronic gouty arthropathy. In addition, patients had to have been treated unsuccessfully (due to intolerance or inadequate response) with a urate-lowering treatment, or had to have a contraindication to urate-lowering treatments. Inadequate response to therapy was defined as serum urate not being reduced to 6 mg/dl despite at least 3 months of treatment with doses of urate-lowering treatment deemed appropriate by the treating physician.
  • Incidence ( A ) and frequency ( B ) of investigator‐reported gout flare during pegloticase treatment in the intent‐to‐treat (ITT) and completer populations (all treatment regimens combined). Differences over time in gout flare incidence were not statistically significant.
  • Efficacy end points. A , Weekly mean plasma urate (PUA) concentrations during the study in the intent‐to‐treat (ITT) population, by treatment group. SUA = serum urate. B , Proportion of treatment responders in the ITT and completer populations, by treatment group. C , Percentage of time without hyperuricemia in the ITT and completer populations, by treatment group.
  • Photographic and radiographic evidence of tophus resolution after pegloticase treatment in patient 1. A, Large draining tophus on fifth distal interphalangeal (DIP) joint, before treatment. C, Corresponding radiograph showing soft tissue swelling and bony erosions in fifth DIP joint, before treatment. B, Resolution of tophus on fifth DIP joint after 12 weeks of treatment. D, Corresponding radiograph showing resolution of soft tissue swelling in fifth DIP joint, a decrease in bony erosions, and thickening of bone cortex at this joint, 15 months after termination of therapy.
  • Effect of a 12‐week course of pegloticase on tophus size in patient 2. A, Large tophus on fifth proximal interphalangeal joint prior to therapy. B, Resolution of tophus after pegloticase treatment.
  • Figure 1 Mechanisms of Inflammation in Gout. In acute gout, monosodium urate crystals that have undergone phagocytosis activate the NLRP3 inflammasome, leading to secretion of interleukin-1β. In turn, this secretion can induce further production of interleukin-1β and other inflammatory mediators and further the activation of synovial lining cells and phagocytes. Monosodium urate crystals also induce many other inflammatory cytokines (e.g., tumor necrosis factor α [TNF-α], interleukin-6 and 8, leukotrienes, and alarmins) by mechanisms that are both dependent on and independent of interleukin-1. Experimental models of gout have demonstrated a role for the activation of the terminal complement pathway (C5b-9 membrane attack complex) induced by monosodium urate crystals. Binding of interleukin-1β to the interleukin-1 receptor results in signal transduction, leading to altered expression of adhesion molecules and chemokines, which together with the other inflammatory events results in the neutrophil recruitment that is a major driver of the intense inflammation in gout. In chronic gout, with low-grade synovitis and frequently recurring or nonresolving flares, these inflammatory processes are probably ongoing with potentially continued release of inflammatory mediators, including interleukin-1β, in the presence of persistent monosodium urate crystals.
  • Figure 5. Central role of the innate immune system and the NALP3 inflammasome in acute goutMonosodium urate crystals are recognised on the surface of monocytes by innate immune system receptors such as toll-like receptors 2 and 4, fragment-crystallisable receptors and integrins. The crystals are taken up by the cell and recognised by the NALP3 (cryopyrin) inflammasome. Activation of caspase follows, with cleavage of the precursor prointerleukin 1β to active interleukin 1β. The proinflammatory cytokine interleukin 1β is then secreted from the cell, along with interleukin 18 and tumour necrosis factor α. This signal is amplified through the recruitment of other cells and the acute gout attack ensues. [65] , [66] , [67] , [68] and [69] FC=fragment crystallisable.
  • Objectives To evaluate the efficacy of anakinra for patients with acute gout. Methods We reviewed the charts of 10 patients who received anakinra for urate crystal-induced arthritis at the Hospital for Special Surgery since 2007. Demographic information, comorbidities, short-term treatment outcomes, and subsequent flares were reviewed. Results Patients in our study had a high prevalence of comorbidities. All patients received corticosteroids before anakinra treatment. The mean number of anakinra injections was 3.2 per patient (100 mg subcutaneously per day). Six patients had a good response. Three patients had a partial response and 1 patient had no response. Nine patients had documented recurrent flares after discontinuing anakinra (ranging from 3 to 45 days after). Conclusion Anakinra is a therapeutic option for patients with acute urate crystal-induced arthritis who do not respond to or have a contraindication to traditional treatments. Although a short course of anakinra resulted in favorable outcomes for some of our patients, response rates were poorer in our study than in previously published reports, and relapses were common.
  • Objectives To evaluate the efficacy of anakinra for patients with acute gout. Methods We reviewed the charts of 10 patients who received anakinra for urate crystal-induced arthritis at the Hospital for Special Surgery since 2007. Demographic information, comorbidities, short-term treatment outcomes, and subsequent flares were reviewed. Results Patients in our study had a high prevalence of comorbidities. All patients received corticosteroids before anakinra treatment. The mean number of anakinra injections was 3.2 per patient (100 mg subcutaneously per day). Six patients had a good response. Three patients had a partial response and 1 patient had no response. Nine patients had documented recurrent flares after discontinuing anakinra (ranging from 3 to 45 days after). Conclusion Anakinra is a therapeutic option for patients with acute urate crystal-induced arthritis who do not respond to or have a contraindication to traditional treatments. Although a short course of anakinra resulted in favorable outcomes for some of our patients, response rates were poorer in our study than in previously published reports, and relapses were common.
  • Objectives To evaluate the efficacy of anakinra for patients with acute gout. Methods We reviewed the charts of 10 patients who received anakinra for urate crystal-induced arthritis at the Hospital for Special Surgery since 2007. Demographic information, comorbidities, short-term treatment outcomes, and subsequent flares were reviewed. Results Patients in our study had a high prevalence of comorbidities. All patients received corticosteroids before anakinra treatment. The mean number of anakinra injections was 3.2 per patient (100 mg subcutaneously per day). Six patients had a good response. Three patients had a partial response and 1 patient had no response. Nine patients had documented recurrent flares after discontinuing anakinra (ranging from 3 to 45 days after). Conclusion Anakinra is a therapeutic option for patients with acute urate crystal-induced arthritis who do not respond to or have a contraindication to traditional treatments. Although a short course of anakinra resulted in favorable outcomes for some of our patients, response rates were poorer in our study than in previously published reports, and relapses were common.
  • Objectives To evaluate the efficacy of anakinra for patients with acute gout. Methods We reviewed the charts of 10 patients who received anakinra for urate crystal-induced arthritis at the Hospital for Special Surgery since 2007. Demographic information, comorbidities, short-term treatment outcomes, and subsequent flares were reviewed. Results Patients in our study had a high prevalence of comorbidities. All patients received corticosteroids before anakinra treatment. The mean number of anakinra injections was 3.2 per patient (100 mg subcutaneously per day). Six patients had a good response. Three patients had a partial response and 1 patient had no response. Nine patients had documented recurrent flares after discontinuing anakinra (ranging from 3 to 45 days after). Conclusion Anakinra is a therapeutic option for patients with acute urate crystal-induced arthritis who do not respond to or have a contraindication to traditional treatments. Although a short course of anakinra resulted in favorable outcomes for some of our patients, response rates were poorer in our study than in previously published reports, and relapses were common.
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  • Pain relief, time to recurrent gout flare, and C‐reactive protein (CRP) levels over the course of the study in patients with acute gouty arthritis treated with canakinumab (10–150 mg) or triamcinolone acetonide (40 mg). A, Least squares (LS) mean change from baseline in pain intensity (as assessed using a 100‐mm visual analog scale) following administration of canakinumab 10–150 mg or triamcinolone acetonide 40 mg. Bars show the mean ± SEM. ∗︁ = P < 0.05 versus triamcinolone acetonide 40 mg. B, Time to first acute gout flare recurrence after treatment, according to the Kaplan‐Meier estimate. Incidence of flare at 8 weeks was 3.6% in the 10 mg group (n = 1), 10.3% in the 25 mg group (n = 3), 3.6% in the 50 mg group (n = 1), 13.8% in the 90 mg group (n = 4), 3.7% in the 150 mg group (n = 1), and 45.4% in the triamcinolone acetonide 40 mg group (n = 25) ( P ≤ 0.01 for all doses of canakinumab versus triamcinolone acetonide). C, Median CRP levels following administration of canakinumab 10–150 mg or triamcinolone acetonide 40 mg. The upper limit of normal (ULN) is 3.0 mg/liter.
  • Dose response curve showing predicted pain intensity 72 hours after treatment, as determined using a 100 mm visual analog scale (VAS). The predicted response and 95% confidence interval (95% CI) are shown. The predictions were estimated from mean baseline VAS and baseline body mass index values.
  • Requested approval for patients with gouty arthritis attacks who do not achieve an adequate response to NSAIDS or colchicine
  • (A) Pain responder analysis. Last observation carried forward (LOCF) (n=10). (B) Pain responder analysis. LOCF (n=10). *Week 2 to day 0; **week 4 vs week 2; †week 6 vs week 2; ‡week 8 vs week 2.
  • Gota: Avances Diagnosticos, Terapéuticos y Rol de los Biológicos

    1. 1. Gota: Avances Diagnosticos, Terapéuticos y Rol de los Biológicos Andy Abril MD Assistant Professor of Rheumatology Director Rheumatology Fellowship Mayo Clinic Florida
    2. 2. OBJETIVOS <ul><li>Conceptos b á sicos demogr á ficos </li></ul><ul><li>Avances diagn ó sticos </li></ul><ul><li>Avances terape ú ticos </li></ul>
    3. 3. AUMENTO DE LA INCIDENCIA Arromdee et al. J Rheumatol . 2002;29:2403-2406 . Incidence rates x 100,000 Age at diagnosis of gout, years <ul><ul><li>La tasa de gota primaria se ha doblado atraves de 18 años, Rochester, MN </li></ul></ul>500 400 300 200 100 0 0 20 40 60 80 100 Hombres , 1995-1996 Hombres , 1977-1978 Mujeres , 1995-1996 Mujeres , 1977-1978
    4. 4. La Prevalencia va en Aumento <ul><li># Casos ↑ de 2.9 por 1000 en 1990 a 5.2 por 1000 en 1999 </li></ul><ul><ul><li>Datos de medicina primaria 1990-1999 </li></ul></ul>Kramer. Am J Kidney Disease. 2002; Roubenoff et al. Rheum Dis Clin North Am . 1990; * Wallace et al. J Rheum . 2004. 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 Tasa de prevalencia por 1000 enrolados 0 1 2 3 4 5 6 <ul><ul><li>Año </li></ul></ul>
    5. 5. La Prevalencia va en Aumento NHANES 2007-2008 <ul><li>Datos de 5,707 participantes en el NHANES (National Health and Nutrition Examination Survey) 2007–2008, los autores estimaron la prevalencia de gota e hiperuricemia </li></ul><ul><li>Los autores compararon estimados de 18,825 participantes en NHANES III (1988–1994). </li></ul>Zhu et al. Arthritis and rheumatism, Accepted: Jun 21, 2011
    6. 6. La Prevalencia va en Aumento NHANES 2007-2008 <ul><li>La prevalencia de gota fue de 3.9% (8.3 millones) en adultos en 2007–2008 (5.9% [6.1 millones] en hombres y 2.0% [2.2 millones] en mujeres). </li></ul><ul><li>Datos mas altos que en NHANES III, con diferencias de 1.2% en la prevalencia de gota (95% CI, 0.6 to 1.9), 0.15 mg/dL en AUS (95% CI, 0.07 to 0.24), y 3.2% en la prevalencia de hiperuricemia (95% CI, 1.2 to 5.2). </li></ul>Zhu et al. Arthritis and rheumatism, Accepted: Jun 21, 2011
    7. 7. Aumento de los niveles sericos de acido urico Acido Urico Sérico, mg/dL 1960 1967 1991 2003 Taiwan 1 Taiwan 2 Framingham 3 Tecumseh 4 4.9 5.12 6.14 7.1 0 2 4 6 8 1. Yu K-H. Rheumatology . 2004; 2. Lin. J Rheumatol. 2000; 3. Hall Am J Med. 1967; 4. Mikkelsen. Am J Med. 1965. 6.8 Year
    8. 8. AUMENTO DE PREVALENCIA: Aumento de factores de riesgo <ul><li>Longevidad </li></ul><ul><li>Enfermedad coronaria, ICC, DM </li></ul><ul><li>Hipertensi ó n arterial </li></ul><ul><li>Diureticos y aspirina </li></ul><ul><li>Obesidad / S í ndrome Metab ó lico </li></ul><ul><li>Dieta / alcohol </li></ul><ul><li>Insuficiencia renal terminal </li></ul><ul><ul><li>Transplantes, ciclosporina </li></ul></ul>
    9. 9. Hiperuricemia y Morbimortalidad Cardiovascular Prematura Hiperuricemia  el riesgo de Enfermedad coronaria,cardiopat í a isqu é mica y otros eventos cardiovasculares Hiperuricemia  mortalidad por Enfermedad coronaria,cardiopatía isquémica, y mortalidad en general <ul><li>Breckenridge et al (Lancet. 1966;1:15-18.) </li></ul><ul><li>Framingham Heart Study (Ann Intern Med. 1999;131:7-13.) </li></ul><ul><li>SHEP (J Hypertens. 2000;18:1149-1154.) </li></ul><ul><li>Worksite Treatment Program (J Hypertens. 1998;16:761-769.) </li></ul><ul><li>PIUMA (Hypertension. 2000;36:1072-1078.) </li></ul><ul><li>LIFE 2003 (Kidney Int. 2003;65:1041-1049.) </li></ul><ul><li>Darmawan et al (J Rheum. 2003;30:2437-2443.) </li></ul><ul><li>Lehto et al (Stroke. 1998;29:635-639.) </li></ul><ul><li>NHANES (JAMA. 2000;283:2404-2410.) </li></ul><ul><li>Framingham Heart Study (Ann Intern Med. 1999;131:7-13.) </li></ul><ul><li>Bickel et al (Am J Cardiol. 2002;89:12-17.) </li></ul><ul><li>Darmawan et al (J Rheum. 2003;30:2437-2443.) </li></ul>
    10. 10. Enfermedad cardiovascular y factores de riesgo asociados con hiperuricemia Feig D et al. N Engl J Med 2008;359:1811-1821
    11. 11. Evidencia de la relacion Acido Urico / Hipertension Arterial <ul><li>Acido ú rico elevado predice consistentemente el desarrollo de HTA </li></ul><ul><li>Hiperuricemia presente en el 25-60% de pacientes con HTA esencial no tratada y 90% de los pacientes adolescentes con HTA esencial de comienzo reciente </li></ul><ul><li>El aumento de á cido ú rico en roedores causa HTA con sus caracteristicas fisiol ó gicas e histol ó gicas </li></ul><ul><li>La reducci ó n del á cido ú rico con inhibidores de la xantina oxidasa, disminuye la presion arterial en adolescentes con HTA esencial de comienzo reciente </li></ul>
    12. 12. Hiperuricemia e HTA Feig D et al. N Engl J Med 2008;359:1811-1821
    13. 13. Mecanismo Propuesto para Hipertension Mediada por Acido Urico Feig D et al. N Engl J Med 2008;359:1811-1821
    14. 15. AVANCES DIAGNOSTICOS ULTRASONIDO CT SCAN DE ENERGIA DUAL
    15. 16. ULTRASONIDO
    16. 17. Ultrasonido en Gota <ul><li>Puig JG, de Miguel E, Castillo MC, Rocha AL, Martinez MA,Torres RJ: Asymptomatic hyperuricemia: impact of ultrasonography . Nucleosides Nucleotides Nucleic Acids 2008, 27: 592-595. </li></ul><ul><li>Wright SA. Filippucci E. McVeigh C. Grey A. McCarron M. Grassi W. Wright GD. Taggart AJ: High-resolution ultrasonography of the first metatarsal phalangeal joint in gout: a controlled study. Ann Rheum Dis 2007, 66: 859-864. </li></ul><ul><li>Rettenbacher T,Ennemoser S,Weirich H, Ulmer H, Hartig F, Klotz W, Herold M: Diagnostic imaging of gout: comparison of highresolution US versus conventional X-ray . Eur J Radiol 2008, 18: 621-630. </li></ul>
    17. 18. 4 High-resolution ultrasonography of the first metatarsal phalangeal joint in gout: a controlled study. Wright SA; Filippucci E, et al Annals of the Rheumatic Diseases. 66(7):859-64, 2007 Jul.
    18. 19. © 2007 BMJ Publishing Group Ltd and European League Against Rheumatism. 6
    19. 20. © 2007 BMJ Publishing Group Ltd and European League Against Rheumatism. 7
    20. 21. US and gout
    21. 22. DOUBLE CONTOUR Ralph Thiele, et al
    22. 23. TAC DE DOBLE ENERGIA
    23. 24. TAC DE DOBLE ENERGIA <ul><li>Equipado con dos tubos de rayos-x en vez de uno </li></ul><ul><li>Adquisicion simultanea de im á genes con dos niveles de energ í a (frecuencia) diferentes. </li></ul><ul><li>Materiales diferentes (calcio, á cido ú rico, etc) absorben grados diferentes de radiaci ó n en las dos frecuencias </li></ul><ul><li>Algorritmo de im á genes 3D basado en la absorci ó n de radiaci ó n de dos materiales para separar por colores el calcio del urato </li></ul>
    24. 25. TAC DE DOBLE ENERGIA
    25. 36. AVANCES TERAPEUTICOS <ul><li>URICASAS </li></ul><ul><li>AGENTES BIOLOGICOS </li></ul><ul><ul><li>Anti-IL1 </li></ul></ul>
    26. 37. Reabsorci ó n de Acido Urico
    27. 39. Limitaciones del Probenecid <ul><ul><li>Reducci ó n inadecuada de á cido ú rico </li></ul></ul><ul><ul><li>Adherencia al tratamiento (2 veces al dia) </li></ul></ul><ul><ul><li>Retarda excreci ó n renal de indometacina y aspirina </li></ul></ul><ul><ul><li>Aspirina bloquea por completo el efecto uricos ú rico del probenecid. </li></ul></ul><ul><ul><ul><li>(Bloquea la secrecion tubular de uratos) </li></ul></ul></ul><ul><ul><li>Aumenta niveles sangu í neos de methotrexate </li></ul></ul>
    28. 40. Alopurinol y Oxipurinol Analogos de las purinas y tanto substratos como inhibidores de la xantina oxidasa Xanthine oxidase HO Xantina N N NH OH N OH Acido ú rico N N NH OH HO N Hipoxantina NH N N N OH Xanthine oxidase
    29. 41. Limitaciones del Alopurinol <ul><li>Baja adherencia al tratamiento (50%) </li></ul><ul><li>Ataques de gota al incio </li></ul><ul><li>Rash (~2%) </li></ul><ul><li>Sindrome de hipersensibilidad </li></ul><ul><li>Reduccion lenta de tofos </li></ul><ul><li>Dosis ó ptima es controversial </li></ul><ul><li>Interacci ó n con azatioprine o 6-MP </li></ul>
    30. 42. Febuxostat- Uloric Feb 2009 <ul><ul><li>Inhibici ó n potente con reducci ó n significativa del urato s é rico </li></ul></ul><ul><ul><li>Se puede administrar en insuficiencia renal e insuficiencia hepatica leve o moderada sin ajustes de la dosis </li></ul></ul><ul><ul><li>Seguro efectivo y bien tolerado en pacientes intolerantes al alopurinol </li></ul></ul>Swan et al. Arthritis Rheum. 2003; Khosravan et al. Arthritis Rheum. 2004; Becker et al. Arthritis Rheum. 2004. Inhibidor no pur í nico de la xantina oxidasa N N NH N OH Alopurinol Febuxostat O NC N CO 2 H S CH 3 CH 3 H 3 C
    31. 43. Febuxostat Compared with Allopurinol in Patients with Hyperuricemia and Gout Michael A. Becker, M.D., H. Ralph Schumacher Jr., M.D., Robert L. Wortmann, M.D., Patricia A. MacDonald, B.S.N., N.P., Denise Eustace, B.A., William A. Palo, M.S., Janet Streit, M.S. and Nancy Joseph-Ridge, M.D. N Engl J Med Volume 353;23:2450-2461 December 8, 2005
    32. 44. Flujo de Participantes Becker, M. et al. N Engl J Med 2005;353:2450-2461
    33. 45. Pacientes que requirieron tratamiento para ataques de gota Becker, M. et al. N Engl J Med 2005;353:2450-2461
    34. 46. Febuxostat vs Alopurinol Estudios cl í nicos de fase 3 Alopurinol 300 mg Febuxostat 80 mg Febuxostat 120 mg Sujetos con UAS <6.0 mg/dL , % * * * * * P <.05 Ultimos 3 UAS <6.0 mg/dL Semana 52 UAS <6.0 mg/dL Objetivos primarios Becker et al, ACR 2004; NEJM, 2005 Randomizado doble-ciego, 52-semanas, estudio multicentrico de 760 pacientes
    35. 47. Conclusi ó n <ul><li>Febuxostat 80 mg or 120 mg diarios, fue mas efectivo que el alopurinol a la dosis corriente de 300 mg en reducir el á cido ú rico s é rico. </li></ul><ul><li>Reducciones similares de ataques agudos y tofos ocurrieron en todos los grupos </li></ul>
    36. 48. URICASAS
    37. 49. Uricasa Xantina oxidasa Xantina oxidasa
    38. 51. Uricasa Recombinante <ul><li>Rasburicasa </li></ul><ul><ul><li>Indicada en la hiperuricemia del sindrome de lisis tumoral </li></ul></ul><ul><ul><li>Reducciones dram á ticas del á cido ú rico (eg. 10-15 -> 0-2 mg/dl) </li></ul></ul><ul><ul><li>Potencial de disoluci ó n acelerada de tofos gotosos </li></ul></ul>Elitek Package Insert. Sanofi-Synthelabo Inc. 2001. Coiffier et al. J Clin Oncol . 2003
    39. 52. Uricasa-PEG (Pegloticase ) Krystexxa ® <ul><li>Estudios fase 1 </li></ul><ul><ul><li>Eficacia </li></ul></ul><ul><ul><ul><li>Dosis unica IV dose mantuvo niveles de urato serico <6.0 mg/dL por lo menos 14 dias </li></ul></ul></ul><ul><ul><li>Seguridad </li></ul></ul><ul><ul><ul><li>No se detectaron anticuerpos contra uricasa </li></ul></ul></ul><ul><ul><ul><li>Bajos titulos de anticuerpos contra PEG </li></ul></ul></ul><ul><ul><ul><li>Reacciones en el sitio de inyecci ó n y reacciones al é rgicas tardias a la administracion subcutanea </li></ul></ul></ul>
    40. 53. Reduction of plasma urate levels following treatment with multiple doses of pegloticase (polyethylene glycol–conjugated uricase) in patients with treatment-failure gout: Results of a phase II randomized study J. Sundy et al, Pegloticase Phase 2 Study Investigators <ul><li>12–14-semanas estudio randomizado, open-label, multicentrico, grupos paralelos de dosis multiples de pegloticase </li></ul><ul><li>41 pacientes randomizados </li></ul><ul><ul><li>12–14 semanas de tratamiento con pegloticase; 4 brazos: </li></ul></ul><ul><ul><ul><li>4 mg cada 2 semanas </li></ul></ul></ul><ul><ul><ul><li>8 mg cada 2 semanas </li></ul></ul></ul><ul><ul><ul><li>8 mg cada 4 semanas </li></ul></ul></ul><ul><ul><ul><li>12 mg cada 4 semanas. </li></ul></ul></ul>Arthritis & Rheumatism Volume 58, Issue 9, pages 2882-2891, 29 AUG 2008 DOI: 10.1002/art.23810
    41. 54. Reduction of plasma urate levels following treatment with multiple doses of pegloticase (polyethylene glycol–conjugated uricase) in patients with treatment-failure gout: Results of a phase II randomized study J. Sundy et al, Pegloticase Phase 2 Study Investigators <ul><li>Pacientes hiperuricemicos (AU 8 mg/dl al inicio) </li></ul><ul><li>Hombres y mujeres adultos (> 18 a ñ os) </li></ul><ul><li>Gota establecida y sintom á tica </li></ul><ul><li>Falla del tratamiento o contraindicacion a los agentes hipouriceminates </li></ul>Arthritis & Rheumatism Volume 58, Issue 9, pages 2882-2891, 29 AUG 2008 DOI: 10.1002/art.23810
    42. 55. Reduction of plasma urate levels following treatment with multiple doses of pegloticase (polyethylene glycol–conjugated uricase) in patients with treatment-failure gout: Results of a phase II randomized study Arthritis & Rheumatism Volume 58, Issue 9, pages 2882-2891, 29 AUG 2008 DOI: 10.1002/art.23810
    43. 56. Reduction of plasma urate levels following treatment with multiple doses of pegloticase (polyethylene glycol–conjugated uricase) in patients with treatment-failure gout: Results of a phase II randomized study Arthritis & Rheumatism Volume 58, Issue 9, pages 2882-2891, 29 AUG 2008 DOI: 10.1002/art.23810
    44. 57. Resoluci ó n de tofos gotosos a las 12 semanas de tratamiento con pegloticasa Arthritis & Rheumatism Volume 58, Issue 11, pages 3632-3634, 30 OCT 2008 DOI: 10.1002/art.23993 http://onlinelibrary.wiley.com/doi/10.1002/art.23993/full#fig1
    45. 58. Resoluci ó n de tofos gotosos a las 12 semanas de tratamiento con pegloticasa Arthritis & Rheumatism Volume 58, Issue 11, pages 3632-3634, 30 OCT 2008 DOI: 10.1002/art.23993
    46. 59. TERAPIA ANTI-IL1
    47. 60. Mecanismo Inflamatorio en Gota. Neogi T. N Engl J Med 2011;364:443-452
    48. 61. IL-1 en Gota
    49. 62. Anakinra's Efficacy is Variable in Refractory Gout: Report of Ten Cases K Chen et al <ul><li>Chart review of 10 patients who received anakinra for urate crystal-induced arthritis at the Hospital for Special Surgery since 2007. </li></ul><ul><li>6 patients had a good response. 3 patients had a partial response and 1 patient had no response. </li></ul><ul><li>9 patients had documented recurrent flares after discontinuing anakinra (ranging from 3 to 45 days after). </li></ul>Seminars in Arthritis and Rheumatism Volume 40, Issue 3 , December 2010, Pages 210-214
    50. 63. Anakinra's Efficacy is Variable in Refractory Gout: Report of Ten Cases K Chen et al <ul><li>Revisi ó n retrospectiva de 10 patients que recibieron anakinra para artritis por urato desde 2007. </li></ul><ul><li>6 pacientes tuvieron buena respuesta; 3 pacientes respuesta parcial y 1 paciente no respondi ó . </li></ul><ul><li>En 9 pacientes se documentaron recurrencias luego de descontinuar el anakinra (rango de 3 a 45 dias despues). </li></ul>Seminars in Arthritis and Rheumatism Volume 40, Issue 3 , December 2010, Pages 210-214
    51. 64. Anakinra's Efficacy is Variable in Refractory Gout: Report of Ten Cases K Chen et al <ul><li>Conclusi ó n </li></ul><ul><ul><li>Anakinra es una opcion terap é utica en pacientes con artritis por gota que no responden o tienen contraindicaciones a tratamientos tradicionales </li></ul></ul><ul><ul><li>Respuesta mas baja comparado con casos previamente reportados y las recurrencias fueron comunes </li></ul></ul>Seminars in Arthritis and Rheumatism Volume 40, Issue 3 , December 2010, Pages 210-214
    52. 65. Anakinra's Efficacy is Variable in Refractory Gout: Report of Ten Cases K Chen et al <ul><li>Conclusion </li></ul><ul><ul><li>Anakinra is a therapeutic option for patients with acute urate crystal-induced arthritis who do not respond to or have a contraindication to traditional treatments. </li></ul></ul><ul><ul><li>A short course of anakinra resulted in favorable outcomes for some of our patients, </li></ul></ul><ul><ul><li>Response rates were poorer in our study than in previously published reports, and relapses were common. </li></ul></ul>Seminars in Arthritis and Rheumatism Volume 40, Issue 3 , December 2010, Pages 210-214
    53. 66. Canakinumab <ul><li>Anticuerpo monoclonal humano con una larga vida media (21–28 dias) </li></ul><ul><li>Bloqueo potente y selectivo de IL-1 </li></ul><ul><li>Inducci ó n de remision completa rapida y sostenida en pacientes con CAPS (Sindrome peri ó dico asociado a criopirinas) </li></ul>
    54. 67. Canakinumab for the Treatment of Acute Flares in Difficult-to-Treat Gouty Arthritis Results of a Multicenter, Phase II, Dose-Ranging Study Alexander So, Marc De Meulemeester, Andrey Pikhlak, A. Eftal Yu¨cel, Dominik Richard, Valda Murphy, Udayasankar Arulmani, Peter Sallstig, and Naomi Schlesing <ul><li>Estudio de 8 semanas </li></ul><ul><li>200 pacientes con gota articular aguda refractaria o con contraindicaciones a los AINES o colchicina </li></ul><ul><li>Randomizados en 2 grupos: </li></ul><ul><ul><li>1- Dosis ú nica SC de canakinumab (10, 25, 50,90, or 150 mg; n = 143) </li></ul></ul><ul><ul><li> 2- Dosis ú nica intramuscular de triamcinolone (40 mg; n = 57). </li></ul></ul><ul><li>Dolor registrado en una escala an á loga visual de 100-mm. </li></ul>Arthritis & Rheumatism Volume 62, Issue 10, pages 3064-3076, 8 JUN 2010 DOI: 10.1002/art.27600
    55. 68. Canakinumab for the treatment of acute flares in difficult to treat gouty arthritis: Results of a multicenter, phase II, dose ranging study Arthritis & Rheumatism Volume 62, Issue 10, pages 3064-3076, 8 JUN 2010 DOI: 10.1002/art.27600
    56. 69. Canakinumab for the treatment of acute flares in difficult to treat gouty arthritis: Results of a multicenter, phase II, dose ranging study Arthritis & Rheumatism Volume 62, Issue 10, pages 3064-3076, 8 JUN 2010 DOI: 10.1002/art.27600
    57. 70. Conclusi ó n <ul><li>C anakinumab 150 mg provee alivio del dolor sostenido y rapido en pacientes con ataques agudos de gota, y reduce significativamente el riesgo de ataques recurrentes comparado con triamcinolona. </li></ul>
    58. 71. FDA <ul><li>Panel de la FDA vota 11-1 en contra de la aprobaci ó n de cankinumab en gota, para la indicacion propuesta </li></ul><ul><li>Questionamientos a la seguridad de la droga </li></ul><ul><ul><li>Falta de informaci ó n a largo plazo </li></ul></ul><ul><ul><li>Vida media prolongada </li></ul></ul><ul><ul><li>Dudas acerca de la incidencia de infecciones y anomalias de laboratorio despues de una dosis ú nica. </li></ul></ul>Rheumatology News vol 10, No7; July 2011
    59. 72. Rilonacept <ul><li>Proteina de fusi ó n de un receptor soluble-Fc </li></ul><ul><li>Se une e inhibe tanto la IL1a como la IL1b </li></ul><ul><li>Efectos durables y rapidos en pacientes con CAPS </li></ul>
    60. 73. The interleukin 1 inhibitor rilonacept in treatment of chronic gouty arthritis: results of a placebocontrolled, monosequence crossover, nonrandomised, single-blind pilot study R Terkeltaub, J S Sundy, H R Schumacher, F Murphy, S Bookbinder, S Biedermann, R Wu, S Mellis, A Radin <ul><li>14- semanas, multicentrico, no randomizado </li></ul><ul><li>Estudio ciego, monosequencia cruzado </li></ul><ul><li>10 pacientes con artritis por gota cr ó nica activa </li></ul><ul><ul><li>1- Curso corto de placebo (2 semanas), </li></ul></ul><ul><ul><li>2- Tratamiento con rilonacept (6 semanas) </li></ul></ul><ul><ul><li>3- Seguimiento de 3-6 semanas post-tratamiento. </li></ul></ul>Ann Rheum Dis 2009;68:1613–1617
    61. 74. Rilonacept for Gout
    62. 76. Conclusiones <ul><li>Rilonacept es generalmente bien tolerado y ofrece beneficio terap é utico al reducir el dolor en pacientes con gota refractaria cr ó nica </li></ul><ul><li>Se necesitan estudios mas amplios de agentes anti-IL1 para esta indicaci ó n espec í fica </li></ul>
    63. 77. RESUMEN <ul><li>El febuxostat es una buena alternativa en pacientes hiperuricemicos que no toleran o no responden al alopurinol </li></ul><ul><li>Las uricasas se deben usar en pacientes refractarios a alopurinol o febuxostat </li></ul><ul><ul><li>Tofos gotosos problematicos o deformantes </li></ul></ul><ul><li>Las terapias biologicas en gota solo se deben considerar en casos refractarios a otras terapias convencionales </li></ul>

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