scholarly journals Pegloticase in gout treatment - safety issues, latest evidence and clinical considerations

2017 ◽  
Vol 8 (12) ◽  
pp. 379-388 ◽  
Author(s):  
Allison Guttmann ◽  
Svetlana Krasnokutsky ◽  
Michael H. Pillinger ◽  
Adey Berhanu

Gout is a common rheumatic condition, with increasing prevalence in recent decades. The mainstay of treatment for gout is oral urate-lowering therapy (ULT), typically with xanthine oxidase inhibitors (XOIs). Unfortunately, a proportion of patients have persistent gout that is refractory to ULT. Pegloticase, a recombinant pegylated uricase, has been approved by the US Food and Drug Administration for the treatment of refractory gout. However, concern has been raised regarding the risk of infusion reactions, which are now understood to be largely due to the development of antipegloticase antibodies. Discontinuation of pegloticase upon failure to lower serum urate has been shown to markedly reduce infusion reaction risk, but deprives patients of what, in many cases, is a last-resort treatment. In this manuscript, we review the rationale, mechanism of action, efficacy and safety of pegloticase. Additionally, we focus on potential strategies to reduce pegloticase immunogenicity and potentially make this important agent available to a wider group of patients requiring treatment.

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 442.2-443 ◽  
Author(s):  
H. Rainey ◽  
H. S. B. Baraf ◽  
A. Yeo ◽  
P. Lipsky

Background:Pegloticase is a mammalian recombinant uricase coupled to monomethoxy polyethylene glycol that is approved in the US for treatment of patients with chronic refractory gout and causes profound reductions in serum urate. However, treatment with pegloticase is limited by the induction of anti-drug antibodies and loss of responsiveness in nearly half of treated patients.Objectives:The goal of this study was to determine whether co-therapy with azathioprine (AZA) would increase the frequency of chronic refractory gout patients who had persistent urate lowering from pegloticase therapy.Methods:This open label multicenter study enrolled subjects with chronic gout who failed to lower serum urate to <6 mg/dL despite medically indicated doses of urate lowering therapy (NCT02598596). Patients were screened for adequate levels of the AZA metabolizing enzyme thiopurine methyl transferase and then started on daily oral AZA 1.25 mg/kg for 1 week and then 2.5 mg/kg for the remainder of the trial. Blood levels of AZA metabolites 6-thioguanine and 6-methylmercaptopurine were measured biweekly. After receiving 2 weeks of AZA, patients were started on pegloticase (8 mg IV) and were treated biweekly for 24 weeks. The primary endpoint was the persistent lowering of serum urate to <6 mg/dL at the last three consecutive study visits. Patients who had an increase in serum urate to >6 mg/dL while on therapy did not receive additional pegloticase. All patients received infusion prophylaxis with hydrocortisone as well as gout flare prophylaxis.Results:To date, 12 patients have been enrolled. All patients were male, 75% white and 25% African American. Mean age was 62.4 ± 14.7 years, the mean BMI was 31.1 ± 4.5 and the mean duration of gout was 13.8 ± 9.2 years. At baseline, all patients had visible tophi; 58.3% suffered from gout flares; 81.8% had hypertension; 45.5% had dyslipidemia and 9.0% had coronary artery disease. Of the 12 patients, 6 have completed the full course of treatment with persistent urate lowering and 2 remain on treatment also with persistent urate lowering (figure). 2 patients lost the urate lowering effect, both after 2 doses of pegloticase, and did not receive additional therapy. 1 patient experienced an infusion reaction during the first dose (1 infusion reaction in 90 infusions [1.1%] in the entire trial to date) and 1 subject had subjective symptoms of AZA intolerance with no laboratory abnormalities; these subjects discontinued the study and were not evaluable for the endpoint. No adverse events related to AZA were reported and gout flares were noted in 6 subjects (mean 1.5 flares/patient with flares).Conclusion:AZA can be used safely in subjects with chronic refractory gout and appears to increase the frequency of subjects experiencing long term lowering of serum urate.References:Disclosure of Interests: :Hope Rainey: None declared, Herbert S.B. Baraf Grant/research support from: Horizon; Gilead Sciences, Inc.; Pfizer; Janssen; AbbVie, Consultant of: Horizon; Gilead Sciences, Inc.; Merck; AbbVie, Speakers bureau: Horizon, Anthony Yeo Employee of: Horizon, Peter Lipsky Consultant of: Horizon Therapeutics


Author(s):  
Prafull Mohan ◽  
Shah Nazar ◽  
Pooja Gupta

Background: Rigorous premarketing trials may fail to capture safety issues associated with new drugs. This is more likely to happen in case of biopharmaceuticals. We take the case of rituximab, and anti CD20 monoclonal antibody, which was the first monoclonal antibody to get approval. This open label observational study was done with the objective of estimating the incidence of acute infusion reaction associated with rituximab infusion.Methods: The study population consisted of patients hospitalized for receiving rituximab, in day care centre(s) of a tertiary care hospital. Number and type of acute infusion reactions (AIR) were recorded on a case record form along with patient characteristics and medical history.Results: A total of 50 infusions were observed and all infusions were followed by at least one AIR. Total 71 AIRs were recorded among these 50 infusions (1.4 AIR per infusion). Non-Hodgkin’s lymphoma was the commonest indication for which patients were receiving rituximab. In a subset analysis, incidence of AIR was statistically lower in patients having received corticosteroids as premedication. However, brand of rituximab, gender of the patient and first or second cycle had no bearing on incidence of AIRs.Conclusions: AIRs are more common in real time clinical settings than what is reported. There is a need to formulate appropriate risk management plan depending on post marketing clinical data. Use of corticosteroids as premedication may be one such strategy. New drugs, esp biopharmaceuticals, may have unidentified/under reported safety issues and there is a need to undertake focussed pharmacovigilance endeavours to unravel them.


2013 ◽  
Vol 40 (6) ◽  
pp. 872-876 ◽  
Author(s):  
Karen Pui ◽  
Peter J. Gow ◽  
Nicola Dalbeth

Objective.Probenecid is recommended as urate-lowering therapy (ULT) in patients with gout where xanthine oxidase inhibitors are ineffective, not tolerated, or contraindicated. The aim of our study was to determine the efficacy of probenecid to achieve serum urate (SU) targets (< 0.36 mmol/l) in clinical practice.Methods.We identified 57 patients prescribed with probenecid from a database of 521 rheumatology clinic attenders with gout. Demographic characteristics, indications for probenecid, probenecid doses, side effects, and laboratory data including estimated glomerular filtration rate (eGFR) and SU were recorded.Results.There were 30/57 (53%) patients treated with probenecid as monotherapy and 27/57 (47%) patients treated with probenecid in combination with allopurinol. Target SU concentrations (< 0.36 mmol/l) were achieved in 10/30 (33%) of the probenecid monotherapy group and 10/27 (37%) of the combination treatment group. Baseline SU concentrations, but not eGFR or probenecid dose, independently predicted achievement of target SU. Target SU was achieved in 5/15 (33%) patients with eGFR < 50 ml/min/1.73 m2. There was no difference in the percentage of patients achieving SU target in those with eGFR < 50 ml/min/1.73 m2 compared with those with eGFR ≥ 50 ml/min/1.73 m2. Adverse events attributed to probenecid were observed in 8/42 (19%) patients with eGFR ≥ 50 ml/min/1.73 m2 and in 2/15 (13%) patients with eGFR < 50 ml/min/1.73 m2.Conclusion.Probenecid has moderate efficacy as ULT in clinical management of patients with complex gout who have a lack of efficacy or intolerance to allopurinol. Patients with chronic kidney disease may respond to probenecid with similar rates of adverse events.


2021 ◽  
Vol 49 (2) ◽  
pp. 321-327
Author(s):  
Jason Gardiner ◽  
Aaron S. Kesselheim

AbstractOver-the-counter (OTC) drugs are ubiquitous in the US. Policymakers have long debated how to modernize the system for making determinations of safety and effectiveness and addressing safety issues with OTC drugs.


2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 282.1-282
Author(s):  
R. Flood ◽  
C. Kirby ◽  
Y. Alammari ◽  
D. Kane ◽  
R. Mullan

Background:Emerging evidence that the joints of asymptomatic hyperuricaemic individuals contain monosodium urate (MSU) deposits and that alternative presentations of foot pain occur in hyperuricaemia suggests that preclinical phases may occur prior to a first episodic gout attack. (1) This case–control study evaluates urate deposition in hyperuricaemic individuals not fulfilling the current gout classification criteria, as well as a potential therapeutic role for urate lowering therapy (ULT).Objectives:To investigate whether ULT reduces non-episodic foot pain in patients who fail to meet ACR/EULAR 2015 gout classification criteria.Methods:Following informed consent, hyperuricaemic individuals with persistent, non-episodic foot pain (n=53) not fulfilling ACR/EULAR 2015 gout classification criteria, were compared with asymptomatic hyperuricaemic controls (n=18). Ultrasound (US) of bilateral first metatarsophalangeal (MTP) joints and features of MSU deposition including double contour (DC) sign, tophus and juxta-articular erosion were recorded. Cases only were treated with febuxostat or allopurinol daily for 6 months. Serum urate, 24-hour and 7-day visual analogue score (VAS) 0–100 mm pain scales and the Manchester Foot Pain and Disability Index (MFPDI) were recorded before treatment and after 3 and 6 months. MTP Ultrasound was repeated after a minimum of 6 months on treatment.Results:53 hyperuricaemic individuals with persistent, non-episodic foot pain not meeting the ACR/EULAR 2015 gout classification criteria were recruited. At baseline MTP US DC sign, erosion and tophus occurred in 62.5%, 20.8% and 49% of cases, respectively. No US features of gout occurred in controls. No significant difference was seen in baseline serum urate between cases (481±14 mg/dL) versus controls (437±14; p=NS). Serum urate in cases fell at 3 months (325±25; p<0.01) and 6 months (248±19; p<0.01). For cases, baseline 24-hour pain VAS (46±3.9) reduced at 3 months (32±4.1; p<0.05) and 6 months (21±5.2; p<0.05) of ULT. The 7-day pain VAS (59±3.9) decreased at 3 months (35±4.5; p<0.05) and 6 months (30±5.3; P<0.05). MFPDI (17±1.4) decreased at 3 month (13±1.8; p=<0.05) and 6 months (11±2.2; p=<0.05). When cases were grouped according to the presence (N=33) or absence (N=18) of DC sign on baseline US, no differences were observed for baseline pain scores. Following ULT however, 24-hour pain VAS were significantly lower in DC positive patients at 3 months (22±4.48 DC positive vs 42±6.14 DC negative; p<0.05) and 6 months (12.±5.4 vs 33±8.4; p<0.05). The 7-day pain VAS were significantly lower in DC positive patients at 3 months (23±4.6 vs 47±6.6; p<0.05) and MFDPI were significantly lower in DC positive patients at 3 months (10±1.9 DC positive vs 19±2.9 DC negative; p<0.05).Conclusion:These findings indicate that persistent, non-episodic foot pain in hyperuricaemia is both associated with US features of MSU deposition and is responsive to ULT. Symptomatic hyperuricaemia occurring prior to episodic gout therefore represents an earlier or alternative disease presentation. Changes to the ACR/ EULAR classification criteria to include non-episodic foot pain in the presence of US features of gout may increase the sensitivity of disease classification at an early stage, leading to improved future treatment strategies and long-term outcomes.References:[1]Stewart S, Dalbeth N, Vandal AC, Rome K. Characteristics of the first metatarsophalangeal joint in gout and asymptomatic hyperuricaemia: A cross-sectional observational study. J Foot Ankle Res. 2015;8(1):1–8.Disclosure of Interests:None declared


Circulation ◽  
2012 ◽  
Vol 125 (suppl_10) ◽  
Author(s):  
Elena Flowers ◽  
Cesar Molina ◽  
Ashish Mathur ◽  
Bradley Aouizerat ◽  
Mintu Turakhia

Background South Asians have increased disk for cardiovascular disease (CVD) that is not captured by traditional risk factors, including TC and LDL-c. Low-density apolipoprotein-B (apoB) containing lipoproteins are heterogeneous in size and composition, and the particles with the greatest triglyceride content are thought to ultimately be the most atherogenic. Specific composition of low-density lipoproteins is not captured by common lipid measures (i.e. TC, LDL-c). A high proportion of triglyceride-rich low-density lipoproteins could be a mechanism for CVD risk in South Asians. Our objective was to compare mean TC, LDL-c, HDL-c, triglycerides, and apoB-triglyceride ratio (an estimate of low-density lipoprotein content) between South Asian-Americans and the US population. Methods We studied 2,876 South Asian adults living in the United States participating in a wellness program. Demographics were obtained by self-report. Lipoprotein levels were measured after 10-hour fast. US population means were calculated from NHANES (2007-2008, n = 5,113). Individuals on lipid-lowering therapy were excluded (780 (33%) South Asians, 1,194 (19%) NHANES). Results LDL-c (118mg/dL vs 116mg/dL, p<0.05) and triglycerides (139mg/dL vs 131 mg/dL, p<0.05) were higher in South Asians than the US population, whereas TC was lower (192mg/dL vs 197 mg/dL, p<0.05). HDL-c was lower in South Asians (46mg/dL vs 52mg/dL, p<0.05). ApoB was not statistically significantly different (93mg/dL vs 92mg/dL, p = 0.1), however the apoB/triglyceride ratio was lower in South Asians (0.8 vs 0.9, p<0.05). After stratifying for age by decade and gender, we found that South Asians have lower HDL-c until the age of 50, and lower apoB/triglyceride ratio until the age of 60, with no substantial differences between men and women. Conclusions Mean TC, LDL-c, and triglycerides were normal in South Asians, however the apoB/triglyceride ratio was lower in South Asians than in the US population. This finding indicates that a higher proportion of low-density lipoproteins in South Asians are of the triglyceride-rich atherogenic type. This may portend non-HDL-c as a better indicator of CVD risk than LDL-c in South Asians. Further, low apoB/triglyceride ratio and low HDL-c occurs at a young age in South Asians, suggesting that onset of risk is early. The disappearance of these patterns after age 60 may be the result of sample bias (excluding individuals on lipid lowering therapy), and/or survival bias.


2021 ◽  
Vol 12 ◽  
Author(s):  
Zijing Ran ◽  
Xiaomei Xue ◽  
Lin Han ◽  
Robert Terkeltaub ◽  
Tony R. Merriman ◽  
...  

ObjectiveTo clarify the relationship between serum urate (SU) decrease and visceral fat area (VFA) reduction in patients with gout.MethodsWe retrospectively analyzed 237 male gout patients who had two sets of body composition and metabolic measurements within 6 months. Subjects included had all been treated with urate-lowering therapy (ULT) (febuxostat 20–80 mg/day or benzbromarone 25–50 mg/day, validated by the medical record). All patients were from the specialty gout clinic of The Affiliated Hospital of Qingdao University. The multiple linear regression model evaluated the relationship between change in SU [ΔSU, (baseline SU) – (final visit SU)] and change in VFA [ΔVFA, (baseline VFA) – (final visit VFA)].ResultsULT resulted in a mean (standard deviation) decrease in SU level (464.22 ± 110.21 μmol/L at baseline, 360.93 ± 91.66 μmol/L at the final visit, p &lt;0.001) accompanied by a decrease in median (interquartile range) VFA [97.30 (81.15–118.55) at baseline, 90.90 (75.85–110.05) at the final visit, p &lt; 0.001]. By multiple regression model, ΔSU was identified to be a significant determinant variable of decrease in VFA (beta, 0.302; p = 0.001).ConclusionsThe decrease in SU level is positively associated with reduced VFA. This finding provides a rationale for clinical trials to affirm whether ULT promotes loss of visceral fat in patients with gout.


Author(s):  
Shigeru Nakagaki ◽  
Ryoichi Matsunuma ◽  
Kei Yamaguchi ◽  
Ryosuke Hayami ◽  
Michiko Tsuneizumi

Aims:Pertuzumab plus trastuzumab and docetaxel is a standard regimen for human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the metastatic, adjuvant, and neoadjuvant settings. Infusion reaction represents one of the common side effects of anti-HER2 agents. There is no standard premedication to prevent infusion reactions, although antihistamines, acetaminophen, and/or corticosteroids are often used for this purpose. This study evaluated the ability of premedication to prevent induction reactions in patients receiving pertuzumab, trastuzumab, and docetaxel. Methods: This retrospective, single-institute study assessed infusion reactions in 72 women with HER2-positive early breast cancer who received pertuzumab, trastuzumab, and docetaxel between November 2018 and April 2021. Thirty-six patients received premedication consisting of oral acetaminophen prior to pertuzumab and trastuzumab administration and dexamethasone and D-chlorpheniramine maleate intravenously prior to docetaxel administration (previous regimen). Thirty-six patients received premedication consisting of acetaminophen, dexamethasone, and D-chlorpheniramine maleate sequentially prior to pertuzumab, trastuzumab, and docetaxel administration (current regimen). Results: The rates of infusion reaction after the initial injection were 55.6 and 16.7% in the previous and current regiment groups, respectively (p = 0.001). Trastuzumab more frequently caused infusion reactions than pertuzumab and docetaxel. Chills, vomiting, and nausea were the major symptoms of infusion reactions. Conclusion: Premedication featuring the upfront use of dexamethasone and D-chlorpheniramine maleate prior to the administration of anti-HER2 targeted agents significantly prevented infusion reactions.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 6075-6075
Author(s):  
Daniel Osei-Fofie ◽  
Julie Wetter ◽  
Greg A. Landers ◽  
Peter Alfred Kraus ◽  
Shawgi Sukumaran ◽  
...  

6075 Background: OM is a common, painful, and costly toxicity associated with cytotoxic regimens used to treat H&N cancers, which may result in radiotherapy treatment interruptions to negatively impact tumor control. There are currently no approved interventions to successfully prevent or delay OM onset among patients being treated with radiation therapy, with or without concomitant chemotherapy (CRT). Oxidative stress is a critical event in OM’s pathogenesis. Through its effect on Nrf2, ST-617 has marked anti-oxidative activity/properties. Supportive Therapeutics is developing ST-617, a dithioethione, for the attenuation of OM onset, duration and severity. The objective of this trial was to assess the safety, tolerability, PK, PD and efficacy of ST-617 in patients at high risk of severe OM (SOM). Methods: A dose escalation trial in which ST-617 administered as an oral suspension, 1-2 hours before the administration of daily RT fractions was performed at 9 study sites in South Africa and Australia. Eighteen patients with diagnoses of oral or oropharyngeal CA were enrolled (up to 6 pts/dose). Patients received concomitant cisplatin either weekly or tri-weekly. ST-617 was administered 3 days prior to CRT, and then continuing daily until the end of treatment. Safety outcomes, using CTCAE criteria (v 4.03) were used. Dose escalation occurred in the absence of toxicity. OM occurrence and severity were assessed by trained and validated evaluators using WHO, NCI-CTC and RTOG criteria; scores were centrally assigned. The primary efficacy endpoints included the incidence and duration of SOM (WHO grades 3 or 4) vs historical controls. PD tracking measured total ROS/RNS, GSH/GSSG, regulation in plasma and buccal epithelial cells. Results: 17 pts completed the 50, 100 and 150mg/day with no safety issues. No early dose limiting toxicity (DLT) or serious Adverse Event linked to ST-617 were observed. AEs observed were mainly nausea which is usually associated with CRT as expected. The 100 mg/day dose has been well tolerated with no grade 4 OM. No CRT dose interruptions or delays due to OM has been observed. Total ROS/RNS levels in plasma and buccal samples show significant decrease with increased ST-617 dosing from 50 to 100 mg/day. Conclusions: ST-617 administration was safe at all doses tested. The course and severity of patients treated with ST-617 compared favorably with historical controls. Mechanistic correlation between ROS/RNS levels was seen. A randomized, controlled, double blind trial is planned with the recommended dose of 100mg/day. Clinical trial information: 20180138.


Rheumatology ◽  
2019 ◽  
Vol 58 (12) ◽  
pp. 2177-2180 ◽  
Author(s):  
Gurkirpal Singh ◽  
Bharathi Lingala ◽  
Alka Mithal

Abstract Objectives Several recent observations have suggested that the prevalence of gout may be increasing worldwide, but there are no recent data from the USA. We analysed the prevalence of hyperuricaemia and gout in the US population from 2007–08 to 2015–16. Methods We studied adults ⩾20 years of age from the National Health and Nutrition Examination Survey from 2007–08 to 2015–16. Persons with gout were identified from the home interview question ‘Has a doctor or other health professional ever told you that you had gout?’ Hyperuricaemia was defined as a serum urate level >0.40 mmol/l (6.8 mg/dl) (supersaturation levels at physiological temperatures and pH). Results In 2015–16, the overall prevalence of gout among US adults was 3.9%, corresponding to a total affected population of 9.2 million. Hyperuricaemia (>0.40 mmol/l or 6.8 mg/dl) was seen in 14.6% of the US population (estimated 32.5 million individuals). No significant trends were identified in the age-adjusted prevalence of gout and hyperuricaemia. Statistical comparisons between 2007–08 and 2015–16 age-adjusted rates were not significant. Conclusion While the age-adjusted prevalence of gout and hyperuricaemia has remained unchanged in the most recent decade from 2007–08 to 2015–16, the estimated total number of persons with self-reported gout has increased from 8.3 million to 9.2 million. The age-adjusted prevalence of hyperuricaemia has declined slightly, but the total number of affected individuals is virtually identical (32.5 million in 2015–16 compared with 32.1 million in 2007–08).


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