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John S. Sundy - One of the best experts on this subject based on the ideXlab platform.
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infusion related reactions with Pegloticase a recombinant uricase for the treatment of chronic gout refractory to conventional therapy
Jcr-journal of Clinical Rheumatology, 2014Co-Authors: Herbert S B Baraf, John S. Sundy, Faith D Ottery, Robert A Yood, Michael BeckerAbstract:BackgroundIn clinical trials of Pegloticase, a PEGylated uricase developed for treatment of gout refractory to conventional therapy, infusion-related reactions (IRs) were the second most frequent adverse event reported.ObjectiveThe objective of this study was to provide a detailed account of IRs wit
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induced and pre existing anti polyethylene glycol antibody in a trial of every 3 week dosing of Pegloticase for refractory gout including in organ transplant recipients
Arthritis Research & Therapy, 2014Co-Authors: Michael S Hershfield, John S. Sundy, Nancy J Ganson, Susan J Kelly, Edna Scarlett, Denise JaggersAbstract:Pegloticase, a PEGylated recombinant porcine uricase, is approved for treating refractory gout at a dose of 8 mg intravenous (IV) every 2 weeks. However, during phase 1 testing, pharmacokinetics supported less frequent dosing. Also, single doses of Pegloticase unexpectedly induced antibodies (Ab) that bound to polyethylene glycol (PEG). We have conducted a phase 2 trial to evaluate every 3-week dosing, and to further define the Ab response to Pegloticase. Organ transplant recipients were included, as they are prone to severe gout that is difficult to manage, and because treatment to prevent graft rejection might influence the immune response to Pegloticase. Plasma uricase activity (pUox), urate concentration (pUA), and clinical response were monitored during up to 5 infusions in 30 patients, including 7 organ transplant recipients. Depending on whether pUA <6 mg/dL was achieved and maintained, patients were classified as non (NR), persistent (PR), or transient (TR) responders. Ab to Pegloticase and 10 kDa mPEG were monitored by enzyme linked immunosorbent assay and specificity was further defined. We observed 17 PR, 12 TR, and 1 NR; 21 patients (16 PR, 5 TR) received all 5 infusions. Over the 15-week trial, pUA in PR averaged 1.0 ± 0.4 mg/dL; T ½ for pUox was approximately 13 days, and area under the curve after dose 5 was approximately 30% higher than after dose 1. PR showed clinical benefit and in some, tophi resolved. In 11 of 12 TR, pUox fell rapidly and hyperuricemia recurred before dose 2. In all TR and NR, loss of response to Pegloticase was accompanied by Ab to PEG, which was pre-existing in half of those who had no prior exposure to Pegloticase. No PR, and 1 one out of 7 organ transplant recipients, had a sustained Ab response to Pegloticase. Every 3-week dosing is effective and may enhance the utility of Pegloticase for treating refractory gout. Ab to PEG, which were pre-existing or induced by treatment, caused rapid loss of efficacy and increased the risk of infusion reactions. Organ transplant recipients can benefit from Pegloticase, and may be less prone than non-recipients to developing anti-PEG Ab. Investigation of immunosuppressive strategies to minimize anti-PEG Ab is warranted. ClincalTrials.gov identifier: NCT00111657
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Pegloticase immunogenicity: the relationship between efficacy and antibody development in patients treated for refractory chronic gout
Arthritis Research & Therapy, 2014Co-Authors: Peter E. Lipsky, John S. Sundy, Leonard H Calabrese, Arthur Kavanaugh, Marsha Wolfson, David Wright, Michael BeckerAbstract:The efficacy of Pegloticase, a polyethylene glycol (PEG)-conjugated mammalian recombinant uricase, approved for chronic refractory gout, can be limited by the development of antibodies (Ab). Analyses from 2 replicate, 6-month, randomized controlled trials were performed to characterize Ab responses to Pegloticase. Anti-Pegloticase, anti-PEG, and anti-uricase Ab were determined by validated enzyme-linked immunosorbent assays. Ab titers were analyzed for possible relationships with serum Pegloticase concentrations, serum uric acid (sUA) lowering, and risk of infusion reactions (IRs). Sixty-nine (41%) of 169 patients receiving Pegloticase developed high titer anti-Pegloticase Ab (> 1:2430) and 40% (67/169) developed anti-PEG Ab; 1 patient receiving placebo developed high titer anti-Pegloticase Ab. Only 14% (24/169) of patients developed anti-uricase Ab, usually at low titer. In responders, patients showing sustained UA lowering, mean anti-Pegloticase titers at week 25 (1:837 ± 1687 with biweekly and 1:2025 ± 4506 with monthly dosing) were markedly lower than in nonresponders (1:34,528 ± 42,228 and 1:89,658 ± 297,797, respectively). Nonresponder status was associated with reduced serum Pegloticase concentrations. Baseline anti-Pegloticase Ab, evident in 15% (31/212) of patients, did not predict subsequent loss of urate-lowering response. Loss of sUA response preceded IRs in 44 of 56 (79%) Pegloticase-treated patients. Loss of responsiveness to Pegloticase is associated with the development of high titer anti-Pegloticase Ab that increase clearance of Pegloticase and are associated with a loss of the sUA lowering effect and increased IR risk. Pre-infusion sUA can be used as a surrogate for the presence of deleterious anti-Pegloticase Ab. NCT00325195 . Registered 10 May 2006, NCT01356498 . Registered 27 October 2008.
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exploratory study of radiographic change in patients with tophaceous gout treated with intensive urate lowering therapy
Arthritis Care and Research, 2014Co-Authors: Nicola Dalbeth, John S. Sundy, Anthony Doyle, Fiona M Mcqueen, Herbert S B BarafAbstract:Objective Tophi are strongly associated with structural damage in gout, and urate-lowering therapy reduces tophus size. Pegloticase leads to dramatic reductions in serum urate and subcutaneous tophi in treatment responders. The aim of this analysis was to examine whether profound urate lowering can alter radiographic findings in gout. Methods Serial plain radiographs of the hands and feet were obtained from 8 patients with tophaceous gout treated with Pegloticase. Radiographs were scored for erosion and joint space narrowing (JSN) according to the gout-modified Sharp/van der Heijde method. Scorers were blinded to each other's scores and to the clinical characteristics of the patients (including the clinical response to Pegloticase). A detailed qualitative site-by-site analysis was undertaken to define additional changes observed from baseline. Results All patients experienced a profound urate-lowering response (serum urate level <1 mg/dl) during Pegloticase treatment. For the entire group, the median total radiographic scores reduced from 69.25 (range 1.5–138) at baseline to 57.25 (range 1.5–110) at 12 months (P = 0.02). Median erosion scores reduced over 1 year (P = 0.008), but JSN scores did not change (P = 0.50). Further reductions were observed in total scores and erosion scores in 5 patients with 24-month followup films (one-way analysis of variance P = 0.009 for total score, 0.02 for erosion, and 0.95 for JSN). Qualitative site-by-site analysis identified regression of soft tissue masses, increased sclerosis, and filling in of erosions in the followup films. Conclusion This exploratory study suggests that profound urate lowering can lead to improvement in structural damage, particularly bone erosion, in patients with tophaceous gout.
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tophus burden reduction with Pegloticase results from phase 3 randomized trials and open label extension in patients with chronic gout refractory to conventional therapy
Arthritis Research & Therapy, 2013Co-Authors: Herbert S B Baraf, John S. Sundy, Michael Becker, Sergio R Gutierrezurena, Edward L Treadwell, Janitzia Vazquezmellado, Claudia Rehrig, Faith D Ottery, Robert A YoodAbstract:Two replicate randomized, placebo-controlled six-month trials (RCTs) and an open-label treatment extension (OLE) comprised the Pegloticase development program in patients with gout refractory to conventional therapy. In the RCTs, approximately 40% of patients treated with the approved dose saw complete response (CR) of at least one tophus. Here we describe the temporal course of tophus resolution, total tophus burden in patients with multiple tophi, tophus size at baseline, and the relationship between tophus response and urate-lowering efficacy. Baseline subcutaneous tophi were analyzed quantitatively using computer-assisted digital images in patients receiving Pegloticase (8 mg biweekly or monthly) or placebo in the RCTs, and Pegloticase in the OLE. Tophus response, a secondary endpoint in the trials, was evaluated two ways. Overall tophus CR was the proportion of patients achieving a best response of CR (without any new/enlarging tophi) and target tophus complete response (TT-CR) was the proportion of all tophi with CR. Among 212 patients randomized in the RCTs, 155 (73%) had ≥1 tophus and 547 visible tophi were recorded at baseline. Overall tophus CR was recorded in 45% of patients in the biweekly group (P = 0.002 versus placebo), 26% in the monthly group, and 8% in the placebo group after six months of RCT therapy. TT-CR rates at six months were 28%, 19%, and 2% of tophi, respectively. Patients meeting the primary endpoint of sustained urate-lowering response to therapy (responders) were more likely than nonresponders to have an overall tophus CR at six months (54% vs 20%, respectively and 8% with placebo). Both overall tophus CR and TT-CRs increased with treatment duration in the OLE, reaching 70% (39/56) of patients and 55% (132/238) of target tophi after one year of treatment in patients receiving Pegloticase during both the RCTs and OLE. At that time point, more tophi had resolved in responders (102/145 or 70% of tophi) than nonresponders (30/93; 32%). Pegloticase reduced tophus burden in patients with refractory tophaceous gout, especially those achieving sustained urate-lowering. Complete resolution of tophi occurred in some patients by 13 weeks and in others with longer-term therapy. NCT00325195 , NCT01356498
Herbert S B Baraf - One of the best experts on this subject based on the ideXlab platform.
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Infusion-Related Reactions With Uricase for the Treatment of
2016Co-Authors: Herbert S B Baraf, Robert A Yood, Michael A, Pharmaceuticals IncAbstract:oped for treatment of gout refractory to conventional therapy, infusion-related reactions (IRs) were the second most frequent adverse event reported. Objective: The objective of this study was to provide a detailed account of IRs with Pegloticase therapy. Methods: Data from 2 replicate, 6-month randomized trials and an open-label extension study were pooled. Infusions of Pegloticase (8 mg) were administered biweekly or monthly; all patients received prophylaxis (antihistamine, acetaminophen, and corticosteroid) and were tested for urate levels prior to each infusion. An IR was defined by protocol as any otherwise unexplained adverse event or cluster of temporally related events occurring during or within 2 hours of infusion. Results: Infusion-related reactions occurred in 94 (45%) of 208 patients receiving Pegloticase; 10 patients reported IRs at first infusion and 84 during subsequent infusions. Chest discomfort (15%), flushing (12%), and dyspnea (11%) were the most common symptoms. Most IRs were ORIGINAL ARTICLEand the most common reason for discontinuation in the RCTs. Furthermore, post hoc analyses of data from the RCTs revealed relationships between urate-lowering responses to Pegloticase therapy, the development of Pegloticase antibodies, and the risk for IRs. These relationships were not appreciated while the RCTs were in progress because investigators were blinded to uric acid levels and the study treatments, but they provide critical insight Sobi. He previously consulted for and received support from Savien
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infusion related reactions with Pegloticase a recombinant uricase for the treatment of chronic gout refractory to conventional therapy
Jcr-journal of Clinical Rheumatology, 2014Co-Authors: Herbert S B Baraf, John S. Sundy, Faith D Ottery, Robert A Yood, Michael BeckerAbstract:BackgroundIn clinical trials of Pegloticase, a PEGylated uricase developed for treatment of gout refractory to conventional therapy, infusion-related reactions (IRs) were the second most frequent adverse event reported.ObjectiveThe objective of this study was to provide a detailed account of IRs wit
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exploratory study of radiographic change in patients with tophaceous gout treated with intensive urate lowering therapy
Arthritis Care and Research, 2014Co-Authors: Nicola Dalbeth, John S. Sundy, Anthony Doyle, Fiona M Mcqueen, Herbert S B BarafAbstract:Objective Tophi are strongly associated with structural damage in gout, and urate-lowering therapy reduces tophus size. Pegloticase leads to dramatic reductions in serum urate and subcutaneous tophi in treatment responders. The aim of this analysis was to examine whether profound urate lowering can alter radiographic findings in gout. Methods Serial plain radiographs of the hands and feet were obtained from 8 patients with tophaceous gout treated with Pegloticase. Radiographs were scored for erosion and joint space narrowing (JSN) according to the gout-modified Sharp/van der Heijde method. Scorers were blinded to each other's scores and to the clinical characteristics of the patients (including the clinical response to Pegloticase). A detailed qualitative site-by-site analysis was undertaken to define additional changes observed from baseline. Results All patients experienced a profound urate-lowering response (serum urate level <1 mg/dl) during Pegloticase treatment. For the entire group, the median total radiographic scores reduced from 69.25 (range 1.5–138) at baseline to 57.25 (range 1.5–110) at 12 months (P = 0.02). Median erosion scores reduced over 1 year (P = 0.008), but JSN scores did not change (P = 0.50). Further reductions were observed in total scores and erosion scores in 5 patients with 24-month followup films (one-way analysis of variance P = 0.009 for total score, 0.02 for erosion, and 0.95 for JSN). Qualitative site-by-site analysis identified regression of soft tissue masses, increased sclerosis, and filling in of erosions in the followup films. Conclusion This exploratory study suggests that profound urate lowering can lead to improvement in structural damage, particularly bone erosion, in patients with tophaceous gout.
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tophus burden reduction with Pegloticase results from phase 3 randomized trials and open label extension in patients with chronic gout refractory to conventional therapy
Arthritis Research & Therapy, 2013Co-Authors: Herbert S B Baraf, John S. Sundy, Michael Becker, Sergio R Gutierrezurena, Edward L Treadwell, Janitzia Vazquezmellado, Claudia Rehrig, Faith D Ottery, Robert A YoodAbstract:Two replicate randomized, placebo-controlled six-month trials (RCTs) and an open-label treatment extension (OLE) comprised the Pegloticase development program in patients with gout refractory to conventional therapy. In the RCTs, approximately 40% of patients treated with the approved dose saw complete response (CR) of at least one tophus. Here we describe the temporal course of tophus resolution, total tophus burden in patients with multiple tophi, tophus size at baseline, and the relationship between tophus response and urate-lowering efficacy. Baseline subcutaneous tophi were analyzed quantitatively using computer-assisted digital images in patients receiving Pegloticase (8 mg biweekly or monthly) or placebo in the RCTs, and Pegloticase in the OLE. Tophus response, a secondary endpoint in the trials, was evaluated two ways. Overall tophus CR was the proportion of patients achieving a best response of CR (without any new/enlarging tophi) and target tophus complete response (TT-CR) was the proportion of all tophi with CR. Among 212 patients randomized in the RCTs, 155 (73%) had ≥1 tophus and 547 visible tophi were recorded at baseline. Overall tophus CR was recorded in 45% of patients in the biweekly group (P = 0.002 versus placebo), 26% in the monthly group, and 8% in the placebo group after six months of RCT therapy. TT-CR rates at six months were 28%, 19%, and 2% of tophi, respectively. Patients meeting the primary endpoint of sustained urate-lowering response to therapy (responders) were more likely than nonresponders to have an overall tophus CR at six months (54% vs 20%, respectively and 8% with placebo). Both overall tophus CR and TT-CRs increased with treatment duration in the OLE, reaching 70% (39/56) of patients and 55% (132/238) of target tophi after one year of treatment in patients receiving Pegloticase during both the RCTs and OLE. At that time point, more tophi had resolved in responders (102/145 or 70% of tophi) than nonresponders (30/93; 32%). Pegloticase reduced tophus burden in patients with refractory tophaceous gout, especially those achieving sustained urate-lowering. Complete resolution of tophi occurred in some patients by 13 weeks and in others with longer-term therapy. NCT00325195 , NCT01356498
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Tophus burden reduction with Pegloticase: results from phase 3 randomized trials and open-label extension in patients with chronic gout refractory to conventional therapy
'Springer Science and Business Media LLC', 2013Co-Authors: Herbert S B Baraf, Ottery, Faith D., Sundy, John S., Becker, Michael A., Vazquez-mellado Janitzia, Gutierrez-urena, Sergio R., Treadwell, Edward L., Rehrig, Claudia D., Yood, Robert A.Abstract:INTRODUCTION: Two replicate randomized, placebo-controlled six-month trials (RCTs) and an open-label treatment extension (OLE) comprised the Pegloticase development program in patients with gout refractory to conventional therapy. In the RCTs, approximately 40% of patients treated with the approved dose saw complete response (CR) of at least one tophus. Here we describe the temporal course of tophus resolution, total tophus burden in patients with multiple tophi, tophus size at baseline, and the relationship between tophus response and urate-lowering efficacy. METHODS: Baseline subcutaneous tophi were analyzed quantitatively using computer-assisted digital images in patients receiving Pegloticase (8 mg biweekly or monthly) or placebo in the RCTs, and Pegloticase in the OLE. Tophus response, a secondary endpoint in the trials, was evaluated two ways. Overall tophus CR was the proportion of patients achieving a best response of CR (without any new/enlarging tophi) and target tophus complete response (TT-CR) was the proportion of all tophi with CR. RESULTS: Among 212 patients randomized in the RCTs, 155 (73%) had ≥ 1 tophus and 547 visible tophi were recorded at baseline. Overall tophus CR was recorded in 45% of patients in the biweekly group (P = 0.002 versus placebo), 26% in the monthly group, and 8% in the placebo group after six months of RCT therapy. TT-CR rates at six months were 28%, 19%, and 2% of tophi, respectively. Patients meeting the primary endpoint of sustained urate-lowering response to therapy (responders) were more likely than nonresponders to have an overall tophus CR at six months (54% vs 20%, respectively and 8% with placebo). CONCLUSIONS: Pegloticase reduced tophus burden in patients with refractory tophaceous gout, especially those achieving sustained urate-lowering. Complete resolution of tophi occurred in some patients by 13 weeks and in others with longer-term therapy
Georg Schett - One of the best experts on this subject based on the ideXlab platform.
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development of a dual energy computed tomography scoring system for measurement of urate deposition in gout
Arthritis Care and Research, 2016Co-Authors: Sara Bayat, Lisa K Stamp, Opetaia Aati, J Rech, Mark Sapsford, Alexander Cavallaro, Michael Lell, Elizabeth G Araujo, Christina Petsch, Georg SchettAbstract:Objective To develop a semiquantitative dual-energy computed tomography (DECT) scoring system for measurement of urate deposition in gout. Methods Following a structured review of images, a semiquantitative DECT urate scoring method for foot/ankle scans was developed for testing. This method included 4 regions, each scored 0–3, with a maximum total DECT urate score of 12. DECT scans from 224 patients (182 with gout, 42 without gout) were scored by 2 independent readers. Automated urate volumes were also measured. Paired scans from 8 patients receiving Pegloticase were analyzed, and a timing exercise was undertaken. The properties of the DECT urate score were analyzed according to the Outcome Measures in Rheumatology (OMERACT) filter. Results The interreader intraclass correlation coefficient (95% confidence interval) for the DECT urate score was 0.98 (0.97–0.98). All scored regions contributed to the total DECT urate score. DECT urate scores and volumes were highly correlated (r = 0.91, P 0.05 for volume). The mean ± SD time required for the DECT urate score was 121 ± 2 seconds and for urate volume was 240 ± 2 seconds (P = 2 × 10−31). Conclusion We have developed a novel semiquantitative DECT scoring method for measurement of urate deposition in the feet/ankles. This method fulfills many aspects of the OMERACT filter.
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thu0510 a longitudinal dual energy computed tomography study on the effect of urate lowering therapies on the reduction of tophus burden in patients with chronic gout
Annals of the Rheumatic Diseases, 2016Co-Authors: Hanna Ellmann, Sara Bayat, Alexander Cavallaro, Michael Lell, Elizabeth G Araujo, Isabelle Oliveira, Matthias Englbrecht, S Mendonca, Bernhard Manger, Georg SchettAbstract:Background Dual energy computed tomography (DECT) allows reliably detecting and quantifying tophus burden in patients with chronic gout. Longitudinal studies on the effect of uric acid lowering drug therapy on tophus burden assessed by DECT are currently lacking with the exception of a small study performed in patients treated with Pegloticase (1) Objectives To assess the effects of uric acid lowering drug therapy to reduce tophus volume in patients with chronic gout Methods Follow-up DECT scans were performed in 94 patients with DECT+ chronic gout receiving stable treatment with either allopurinol, febuxostat, benzbromaron or Pegloticase, or had life-style intervention only with no concomitant uric acid lowering drug therapy. Baseline and follow-up scans of both feet captured tophus volume by Syngo DE Gout software (Siemens). Artefacts were manually excluded. Changes in tophus volume were calculated in a descriptive (tophus volume at baseline minus tophus volume at follow-up) and inferential way (Wilcoxon signed-rank test). Demographic data, medication and blood values (CRP, creatinine, serum urate) were recorded at the time of DECT scan. Results 94 patients (75 men and 19 women) were analyzed. Mean disease duration until the first DECT examination was 3.3 years and mean interval between both DECT examinations was 1.5 years. The overall baseline serum uric acid level decreased from 7.3 ± 2.5 mg/dl to 5.9 ± 2.8 mg/dl at follow up. Baseline tophus volume decreased by 77% with allopurinol (p Conclusions Sustained uric acid lowering drug therapy leads to significant reduction of DECT tophus burden in chronic gout patients. Tophus reduction depends on initial tophus volume. References ) Tophus resolution with Pegloticase: a prospective dual-energy CT study. Araujo EG, Bayat S, Petsch C, Englbrecht M, Faustini F, Kleyer A, Hueber AJ, Cavallaro A, Lell M, Dalbeth N, Manger B, Schett G, Rech J. RMD Open. 2015 Jun 17;1(1):e000075. doi: 10.1136/rmdopen-2015-000075. eCollection 2015. Disclosure of Interest None declared
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sat0308 tophus resolution with Pegloticase a prospective dual energy computed tomography study
Annals of the Rheumatic Diseases, 2015Co-Authors: Georg Schett, Sara Bayat, Alexander Cavallaro, Elizabeth G Araujo, Christina Petsch, Matthias Englbrecht, Francesca Faustini, Arnd Kleyer, Axel J Hueber, Michael LellAbstract:Background Refractory gout is a serious medical condition, which leads to massive deposition of uric acid crystals in the body resulting in the formation of tophi. A new highly effective treatment modality based on the administration of recombinant PEGylated uricase (Pegloticase) allows to approach such patients. Pegloticase cleaves uric acid and leads to a profound drop in serum uric acide levels. How this decrease in uric acid in the body affects the resolution of existing tophi is not yet adequately characterized. Objectives To investigate the effect of intensive lowering of serum uric acid levels by Pegloticase on the resolution of tophi in patients with refractory gout. Methods Descriptive study in patients with refractory gout receiving Pegloticase treatment. Serum uric acid levels were measured before and after each infusion. Dual energy computed tomography scans were taken from all patients before the first infusion and after the last infusion. Computerized tophus volumes were calculated for the baseline and follow up assessments and compared with each other. Results Ten patients with refractory gout and baseline mean serum uric acid level of 8.1 mg/dL were enrolled. Pegloticase effectively reduced tophi in all patients showing a decrease in volume by 71.4%. Responders, showing reduction of serum uric acid level below 6 mg/dl during at least 80% of the treatment time, were virtually cleared from tophi (-94.8%). Dependent on their anatomical localization, resolution of tophi showed different dynamics, with articular tophi showing fast and tendon tophi slow resolution. Conclusions Tophi are highly sensitive to Pegloticase treatment, particularly when located at articular sites. Debulking of disease and a tophus-free state can be reached within a few months of Pegloticase treatment. DECT allows for comprehensively assessing tophus burden and monitoring treatment responses. Disclosure of Interest None declared
Michael Lell - One of the best experts on this subject based on the ideXlab platform.
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development of a dual energy computed tomography scoring system for measurement of urate deposition in gout
Arthritis Care and Research, 2016Co-Authors: Sara Bayat, Lisa K Stamp, Opetaia Aati, J Rech, Mark Sapsford, Alexander Cavallaro, Michael Lell, Elizabeth G Araujo, Christina Petsch, Georg SchettAbstract:Objective To develop a semiquantitative dual-energy computed tomography (DECT) scoring system for measurement of urate deposition in gout. Methods Following a structured review of images, a semiquantitative DECT urate scoring method for foot/ankle scans was developed for testing. This method included 4 regions, each scored 0–3, with a maximum total DECT urate score of 12. DECT scans from 224 patients (182 with gout, 42 without gout) were scored by 2 independent readers. Automated urate volumes were also measured. Paired scans from 8 patients receiving Pegloticase were analyzed, and a timing exercise was undertaken. The properties of the DECT urate score were analyzed according to the Outcome Measures in Rheumatology (OMERACT) filter. Results The interreader intraclass correlation coefficient (95% confidence interval) for the DECT urate score was 0.98 (0.97–0.98). All scored regions contributed to the total DECT urate score. DECT urate scores and volumes were highly correlated (r = 0.91, P 0.05 for volume). The mean ± SD time required for the DECT urate score was 121 ± 2 seconds and for urate volume was 240 ± 2 seconds (P = 2 × 10−31). Conclusion We have developed a novel semiquantitative DECT scoring method for measurement of urate deposition in the feet/ankles. This method fulfills many aspects of the OMERACT filter.
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thu0510 a longitudinal dual energy computed tomography study on the effect of urate lowering therapies on the reduction of tophus burden in patients with chronic gout
Annals of the Rheumatic Diseases, 2016Co-Authors: Hanna Ellmann, Sara Bayat, Alexander Cavallaro, Michael Lell, Elizabeth G Araujo, Isabelle Oliveira, Matthias Englbrecht, S Mendonca, Bernhard Manger, Georg SchettAbstract:Background Dual energy computed tomography (DECT) allows reliably detecting and quantifying tophus burden in patients with chronic gout. Longitudinal studies on the effect of uric acid lowering drug therapy on tophus burden assessed by DECT are currently lacking with the exception of a small study performed in patients treated with Pegloticase (1) Objectives To assess the effects of uric acid lowering drug therapy to reduce tophus volume in patients with chronic gout Methods Follow-up DECT scans were performed in 94 patients with DECT+ chronic gout receiving stable treatment with either allopurinol, febuxostat, benzbromaron or Pegloticase, or had life-style intervention only with no concomitant uric acid lowering drug therapy. Baseline and follow-up scans of both feet captured tophus volume by Syngo DE Gout software (Siemens). Artefacts were manually excluded. Changes in tophus volume were calculated in a descriptive (tophus volume at baseline minus tophus volume at follow-up) and inferential way (Wilcoxon signed-rank test). Demographic data, medication and blood values (CRP, creatinine, serum urate) were recorded at the time of DECT scan. Results 94 patients (75 men and 19 women) were analyzed. Mean disease duration until the first DECT examination was 3.3 years and mean interval between both DECT examinations was 1.5 years. The overall baseline serum uric acid level decreased from 7.3 ± 2.5 mg/dl to 5.9 ± 2.8 mg/dl at follow up. Baseline tophus volume decreased by 77% with allopurinol (p Conclusions Sustained uric acid lowering drug therapy leads to significant reduction of DECT tophus burden in chronic gout patients. Tophus reduction depends on initial tophus volume. References ) Tophus resolution with Pegloticase: a prospective dual-energy CT study. Araujo EG, Bayat S, Petsch C, Englbrecht M, Faustini F, Kleyer A, Hueber AJ, Cavallaro A, Lell M, Dalbeth N, Manger B, Schett G, Rech J. RMD Open. 2015 Jun 17;1(1):e000075. doi: 10.1136/rmdopen-2015-000075. eCollection 2015. Disclosure of Interest None declared
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tophus resolution with Pegloticase a prospective dual energy ct study
RMD Open, 2015Co-Authors: Elizabeth G Araujo, Sara Bayat, Alexander Cavallaro, Michael Lell, Christina Petsch, Matthias Englbrecht, Francesca Faustini, Arnd Kleyer, Axel J Hueber, Nicola DalbethAbstract:Objective To investigate the effect of intensive lowering of serum uric acid (SUA) levels by Pegloticase on the resolution of tophi in patients with refractory gout. Methods Descriptive study in patients with refractory gout receiving Pegloticase treatment. SUA levels were measured before and after each infusion. Dual-energy CT (DECT) scans were taken from all patients before the first infusion and after the last infusion. Computerised tophus volumes were calculated for the baseline and follow-up assessments and compared with each other. Results 10 patients with refractory gout and baseline mean SUA level of 8.1 mg/dL were enrolled. Patients were treated for a mean of 13.3 weeks. Pegloticase effectively reduced tophi in all patients showing a decrease in volume by 71.4%. Responders, showing reduction of SUA level below 6 mg/dL during at least 80% of the treatment time, were virtually cleared from tophi (−94.8%). Dependent on their anatomical localisation, resolution of tophi showed different dynamics, with articular tophi showing fast, and tendon tophi slow, resolution. Conclusions Tophi are highly sensitive to Pegloticase treatment, particularly when located at articular sites. Debulking of disease and a tophus-free state can be reached within a few months of Pegloticase treatment. DECT allows for comprehensively assessing tophus burden and monitoring treatment responses.
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sat0308 tophus resolution with Pegloticase a prospective dual energy computed tomography study
Annals of the Rheumatic Diseases, 2015Co-Authors: Georg Schett, Sara Bayat, Alexander Cavallaro, Elizabeth G Araujo, Christina Petsch, Matthias Englbrecht, Francesca Faustini, Arnd Kleyer, Axel J Hueber, Michael LellAbstract:Background Refractory gout is a serious medical condition, which leads to massive deposition of uric acid crystals in the body resulting in the formation of tophi. A new highly effective treatment modality based on the administration of recombinant PEGylated uricase (Pegloticase) allows to approach such patients. Pegloticase cleaves uric acid and leads to a profound drop in serum uric acide levels. How this decrease in uric acid in the body affects the resolution of existing tophi is not yet adequately characterized. Objectives To investigate the effect of intensive lowering of serum uric acid levels by Pegloticase on the resolution of tophi in patients with refractory gout. Methods Descriptive study in patients with refractory gout receiving Pegloticase treatment. Serum uric acid levels were measured before and after each infusion. Dual energy computed tomography scans were taken from all patients before the first infusion and after the last infusion. Computerized tophus volumes were calculated for the baseline and follow up assessments and compared with each other. Results Ten patients with refractory gout and baseline mean serum uric acid level of 8.1 mg/dL were enrolled. Pegloticase effectively reduced tophi in all patients showing a decrease in volume by 71.4%. Responders, showing reduction of serum uric acid level below 6 mg/dl during at least 80% of the treatment time, were virtually cleared from tophi (-94.8%). Dependent on their anatomical localization, resolution of tophi showed different dynamics, with articular tophi showing fast and tendon tophi slow resolution. Conclusions Tophi are highly sensitive to Pegloticase treatment, particularly when located at articular sites. Debulking of disease and a tophus-free state can be reached within a few months of Pegloticase treatment. DECT allows for comprehensively assessing tophus burden and monitoring treatment responses. Disclosure of Interest None declared
Pascal Richette - One of the best experts on this subject based on the ideXlab platform.
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thu0422 calcium pyrophosphate crystal deposition within tophus lobule a frequent association observed in long time course tophi
Annals of the Rheumatic Diseases, 2020Co-Authors: O Olivier, Pascal Richette, N N Pham, V Frochot, D Bazin, Caroline Marty, Agnes Ostertag, J D Laredo, Q D Nguyen, Thomas BardinAbstract:Background: Pegloticase is an infused biologic approved to treat uncontrolled gout. The drug is highly effective, but patients can develop anti-drug antibodies that interfere with efficacy.1 Randomized clinical trials have shown that 42% of patients treated with bi-weekly Pegloticase had a serum uric acid (sUA) below 6.0 mg/dl at 3 and 6 months.2 Mild-to-moderate immunomodulation has been shown to lower the prevalence of anti-drug antibody formation in patients with other autoimmune diseases (rheumatoid arthritis, Crohn’s disease, juvenile idiopathic arthritis).3 Cases published in the literature suggest that low-to-moderate doses of methotrexate4,5 or azathioprine6 may also attenuate anti-Pegloticase antibody formation in uncontrolled gout patients. Therefore, immunomodulation may allow patients to remain on Pegloticase therapy longer and achieve a more complete therapeutic response. Objectives: To examine Pegloticase treatment response in patients co-treated with methotrexate. Methods: This retrospective chart review included patients from a single community rheumatology practice who began Pegloticase (8 mg every 2 weeks) therapy between January 2017 and September 2019 and were co-treated with methotrexate. Unless contraindicated, methotrexate co-treatment with Pegloticase is now standard in this practice and all patients undergo close monitoring of laboratory parameters including serum uric acid level (sUA), blood counts, and liver function tests (LFTs). To maximize the number of cases, patients administered methotrexate in any form were included. Collected data included demographic information, laboratory values, methotrexate treatment parameters (timing with respect to Pegloticase therapy, dose, route), Pegloticase response parameters (number of infusions, duration of therapy), and adverse events. Main outcome measures included the number of Pegloticase infusions administered (responder defined as ≥12 infusions administered) and therapy duration. Results: Ten patients (9 male) were included. All patients had visible tophi and average patient age was 52.3 ± 13.5 years. Nine patients began subcutaneous methotrexate (25 mg weekly) an average of 19.9 ± 7.0 days (range: 14 to 35 days) before the first Pegloticase infusion. The remaining patient began oral methotrexate (12.5 mg weekly) 14 days after the first Pegloticase infusion. Eight of 10 patients (80%) were considered responders, receiving an average of 15.5 ± 3.8 Pegloticase infusions (range: 12-21 infusions) over 31.8 ± 9.5 weeks (range: 22.1 to 48.3 weeks). In these 8 responders, mean sUA was 0.2 ± 0.0 mg/dL immediately prior to the last Pegloticase infusion. All 10 patients had an initial, rapid decrease in sUA, but two patients discontinued treatment before infusion 12. One patient had increased sUA with a mild infusion reaction, and one patient was lost to follow-up after infusion 5. No new safety concerns emerged. A gout flare occurred in 1 patient and was treated with prednisone. LFT and blood cell parameters were stable over the study period, except in two patients. One had a mild, transient LFT elevation that resolved without treatment, one had an LFT elevation and pancytopenia that improved with methotrexate discontinuation and transfusion, respectively. This patient remained on Pegloticase and continued as a responder. Conclusion: This case series suggests that methotrexate, when used as a co-therapy with Pegloticase, allows more patients to complete therapy and to achieve the full therapeutic response. No new safety concerns emerged. References: [1]Lipsky PE, et al. Arthritis Res Ther 2014;16:R60. [2]Sundy JS, et al. JAMA 2011;306:711-20. [3]Krieckaert CL, et al. Arthritis Res Ther 2010;12:217. [4]Botson J and Peterson J. Ann Rheum Dis. 2019; 78: A1289. [5]Bessen SY, et al. Semin Arthritis Rheum. 2019;49:56-61. [6]Berhanu AA, et al. Semin Arthritis Rheum. 2017;46:754-758. Disclosure of Interests: : John Albert Consultant of: Horizon Therapeutics, Speakers bureau: Horizon Therapeutics, Tony Hosey Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Brian LaMoreaux Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics
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2016 updated eular evidence based recommendations for the management of gout
Annals of the Rheumatic Diseases, 2014Co-Authors: Pascal Richette, Michael Doherty, Eliseo Pascual, V Barskova, Fabio Becce, Johann Castanedasanabria, M Coyfish, S Guillo, T Th L A Jansen, Hein J E M JanssensAbstract:Background New drugs and new evidence concerning the use of established treatments have become available since the publication of the first European League Against Rheumatism (EULAR) recommendations for the management of gout, in 2006. This situation has prompted a systematic review and update of the 2006 recommendations. Methods The EULAR task force consisted of 15 rheumatologists, 1 radiologist, 2 general practitioners, 1 research fellow, 2 patients and 3 experts in epidemiology/methodology from 12 European countries. A systematic review of the literature concerning all aspects of gout treatments was performed. Subsequently, recommendations were formulated by use of a Delphi consensus approach. Results Three overarching principles and 11 key recommendations were generated. For the treatment of flare, colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), oral or intra-articular steroids or a combination are recommended. In patients with frequent flare and contraindications to colchicine, NSAIDs and corticosteroids, an interleukin-1 blocker should be considered. In addition to education and a non-pharmacological management approach, urate-lowering therapy (ULT) should be considered from the first presentation of the disease, and serum uric acid (SUA) levels should be maintained at<6 mg/dL (360 µmol/L ) and <5 mg/dL (300 µmol/L ) in those with severe gout. Allopurinol is recommended as first-line ULT and its dosage should be adjusted according to renal function. If the SUA target cannot be achieved with allopurinol, then febuxostat, a uricosuric or combining a xanthine oxidase inhibitor with a uricosuric should be considered. For patients with refractory gout, Pegloticase is recommended. Conclusions These recommendations aim to inform physicians and patients about the non-pharmacological and pharmacological treatments for gout and to provide the best strategies to achieve the predefined urate target to cure the disease.
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antibodies against polyethylene glycol in healthy subjects and in patients treated with peg conjugated agents
Expert Opinion on Drug Delivery, 2012Co-Authors: Ricardo P. Garay, Raafat Elgewely, Jonathan K Armstrong, George Garratty, Pascal RichetteAbstract:In contrast to the accepted general assumption that polyethylene glycol (PEG) is non-immunogenic and non-antigenic, animal studies clearly showed that uricase, ovalbumin and some other PEGylated agents can elicit antibody formation against PEG (anti-PEG). In humans, anti-PEG may limit therapeutic efficacy and/or reduce tolerance of PEG-asparaginase (PEG-ASNase) in patients with acute lymphoblastic leukemia and of Pegloticase in patients with chronic gout, but did not impair hyposensitization of allergic patients with mPEG-modified ragweed extract or honeybee venom or the response to PEG-IFN in patients with hepatitis C. Of major importance is the recent finding of a 22 – 25% occurrence of anti-PEG in healthy blood donors, compared with a very low 0.2% occurrence two decades earlier. This increase may be due to an improvement of the limit of detection of antibodies during the years and to greater exposure to PEG and PEG-containing compounds in cosmetics, pharmaceuticals and processed food products. These r...
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antibodies against polyethylene glycol in healthy subjects and in patients treated with peg conjugated agents
Expert Opinion on Drug Delivery, 2012Co-Authors: Ricardo P. Garay, Raafat Elgewely, Jonathan K Armstrong, George Garratty, Pascal RichetteAbstract:In contrast to the accepted general assumption that polyethylene glycol (PEG) is non-immunogenic and non-antigenic, animal studies clearly showed that uricase, ovalbumin and some other PEGylated agents can elicit antibody formation against PEG (anti-PEG). In humans, anti-PEG may limit therapeutic efficacy and/or reduce tolerance of PEG-asparaginase (PEG-ASNase) in patients with acute lymphoblastic leukemia and of Pegloticase in patients with chronic gout, but did not impair hyposensitization of allergic patients with mPEG-modified ragweed extract or honeybee venom or the response to PEG-IFN in patients with hepatitis C. Of major importance is the recent finding of a 22 – 25% occurrence of anti-PEG in healthy blood donors, compared with a very low 0.2% occurrence two decades earlier. This increase may be due to an improvement of the limit of detection of antibodies during the years and to greater exposure to PEG and PEG-containing compounds in cosmetics, pharmaceuticals and processed food products. These r...
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Antibodies against polyethylene glycol in healthy subjects and in patients treated with PEG-conjugated agents
Expert Opinion on Drug Delivery, 2012Co-Authors: Ricardo P. Garay, Raafat El-gewely, Jonathan K Armstrong, George Garratty, Pascal RichetteAbstract:In contrast to the accepted general assumption that polyethylene glycol (PEG) is non-immunogenic and non-antigenic, animal studies clearly showed that uricase, ovalbumin and some other PEGylated agents can elicit antibody formation against PEG (anti-PEG). In humans, anti-PEG may limit therapeutic efficacy and/or reduce tolerance of PEG-asparaginase (PEG-ASNase) in patients with acute lymphoblastic leukemia and of Pegloticase in patients with chronic gout, but did not impair hyposensitization of allergic patients with mPEG-modified ragweed extract or honeybee venom or the response to PEG-IFN in patients with hepatitis C. Of major importance is the recent finding of a 22 - 25% occurrence of anti-PEG in healthy blood donors, compared with a very low 0.2% occurrence two decades earlier. This increase may be due to an improvement of the limit of detection of antibodies during the years and to greater exposure to PEG and PEG-containing compounds in cosmetics, pharmaceuticals and processed food products. These results raise obvious concerns regarding the efficacy of PEG-conjugated drugs for a subset of patients. To address these concerns, the immunogenicity and antigenicity of approved PEGylated compounds should be carefully examined in humans. With all these data in hand, patients should be pre-screened and monitored for anti-PEG prior to and throughout a course of treatment with a PEGylated compound. Finally, protein conjugates with the poorly immunogenic hydroxy-PEG sequence or other hydrophilic polymers are in early phases of development and may represent an alternative to immunogenic PEGylated proteins.