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Crystalline Arthritis
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
The MIRROR Randomized Control Trial (Mirror-RCT), currently underway, has enrolled 152 patients to compare the effect of methotrexate versus placebo on pegloticase tolerability and efficacy. If, with the use of immunosuppressives, patients have increased tolerability of pegloticase, it is possible that we may preselect certain gout patients with severe tophaceous disease to initially be treated with several months of pegloticase as a debulking agent prior to transition to a xanthine oxidase inhibitor to reduce their total body urate load more quickly, without subjecting them to adverse effects of pegloticase.
Biotechnology products and indications I. Proteins
Published in Ronald P. Evens, Biotechnology, 2020
Protein enzymes include 31 products, as listed in Table 8.3. The first protein enzyme developed in the late 1980s was alteplase (Activase®), a thrombolytic agent used to minimize complications owing to blood coagulation in acute myocardial infarction. Two further enzymes that were molecularly engineered from alteplase were developed for similar indications. The cardiovascular indications related to thrombolysis have expanded to seven, including acute myocardial infarction, pulmonary embolism, stroke, percutaneous angioplasty, arterial vessel stenting, unstable angina, and acute coronary syndromes with or without unstable angina. A unique enzyme was discovered for cystic fibrosis, dornase alfa, which is the enzyme deficiency responsible for the etiology of this disastrous respiratory disease. Cystic fibrotic patients experience prevention of breakdown of DNA from degrading cells in the lungs, causing sludging of alveolar secretions and very poor lung function. This enzyme was the first protein administered by inhalation, given the nature of the disease being a protein deficiency in the alveoli of lungs. A family of rare single-enzyme deficiencies causes life-ending diseases often in childhood or adolescence, involving multiple organ system disruption (blood, liver, and nervous system). Fifteen such enzyme deficiencies have the replacement enzyme commercially available for 12 diseases, that is, Batten’s, Fabry’s, Gaucher’s, Hunter’s, Hurler’s, Morquio A, Pompe’s, Severe compromised immune disease, Sly, and Maroteaux-Lamy, many of which are specific mucopolysaccharidoses, plus the two diseases with hypophosphatemia and lysosomal acid lipase. Novel rDNA technologies were used primarily to create these replacement enzymes, mitigating the diseases; plus, a gene-activated process was used for a recombinant protein (velaglucerase) and a plant host cell for rDNA for taliglucerase, both products are used in Gaucher’s disease. Two enzymes are available for uric acid abnormalities. Gout is treated with pegloticase. Also, a key enzyme is responsible for uric acid metabolism, principal to the eradication of excess nucleic acid material from dying cells especially in cancers; its deficiency leads to hyperuricemia, and is correctable with the enzyme product rasburicase. Other quite variable and distinct conditions treated with enzyme therapies are acute lymphoblastic leukemia, primary immunodeficiency, Dupuytren’s contracture, methotrexate toxicity, phenylketonuria, and vitreomacular adhesion. Hypodermoclysis (enhancing concurrent drug absorption) involves one enzyme product, Hylenex.
What’s new on the front-line of gout pharmacotherapy?
Published in Expert Opinion on Pharmacotherapy, 2022
Kurt E. G. Blake, Jordan L. Saag, Kenneth G Saag
Pegloticase is a pegylated mammalian uricase indicated for the treatment of chronic refractory gout [19]. The uricase analog converts urate to allantois. Uricase is present in most mammals but absent in humans and higher primates [92]. Pegloticase profoundly lowers serum urate, reduces the tophus burden, as well as improves pain, health-related quality of life and physical function in chronic gout patients [93–95]. Significant immunogenicity of the pegloticase reduces its efficacy due to a need to discontinue therapy once this problem occurs. Anti-drug antibodies (ADA) increase the drug’s clearance and are also strongly associated with potentially serious infusion reactions [96,97]. A rise in serum urate > 6 mg/dl before subsequent infusions is associated with higher titers of anti-drug antibodies against pegloticase [98]. Therefore, pegloticase should be discontinued in non-responders, defined by at least one and likely two serum urates above 6 mg/dl following therapy.
Investigational drugs for hyperuricemia, an update on recent developments
Published in Expert Opinion on Investigational Drugs, 2018
Tristan Pascart, Pascal Richette
Uricase converts uric acid into 5-hydroxyisourate secondarily degraded to the more soluble component allantoin [65]. Lack of a functional uricase in humans explains their relative high SU levels as compared to other mammals. Pegloticase is a mammalian recombinant uricase that has proved to have a very potent urate lowering effect in RCTs [26,27]. Despite a licensing for patients with refractory gouts, pegloticase is only available in the US. The most concerning side effects of pegloticase are infusion-related adverse events possibly related to the occurrence of antidrug antibodies [27,28,66].
Pharmacotherapeutic management of gout in patients with cardiac disease
Published in Expert Opinion on Pharmacotherapy, 2018
It is recognized that hyperuricemia is an independent risk factor for CAD. However, there is paucity of evidence whether treatment of hyperuricemia could lower the risk of CAD. EULAR recommends ULT to be initiated close to the time of the first diagnosis in patients with cardiac comorbidities [26]. However, the American College of Physicians does not share the same opinion as EULAR, in fact, it recommends against initiating ULT in most patients after a first attack [32]. More research regarding this topic needs to be conducted to give us clearer indication for the best timing to initiate ULT and the duration of treatment. Nevertheless, for patients with recurrent flares (≥ 2 per year), tophi, urate arthropathy and/or renal stones, both guidelines have given clear indication to start long-term ULT. ULT like XOI, uricosuric and uricase appear to be safe to be used in patients with CAD. In patients with existing CAD and have normal kidney function, allopurinol, traditional XOI, should be the first line ULT. The second line of ULT should be either switching to febuxostat or a uricosuric or combined allopurinol with a uricosuric if the SUA target cannot be reached after an appropriate dose of allopurinol was given [26]. Pegloticase, only available in certain countries, is reserved for severe refractory cases. There were small number of fatal and non-fatal cardiac events identified in the treatment arm of pegloticase in the two RCTs and OLE, but no cardiac events were identified in the placebo arm. One could argue that given the absence of mechanism that link pegloticase to CAD, the small number of cardiac events could have occurred by chance, and it has nothing to do with the treatment of pegloticase. We need to explore the cardiac safety of pegloticase further to ensure this medication is safe for patients with CAD.