Search

PurposeThyroid eye disease (TED) is a progressive, debilitating and potentially vision-threatening autoimmune disease. Teprotumumab, a novel human monoclonal antibody, has been shown to reverse the clinical manifestations of TED. Patients receiving teprotumumab have been shown in two multicenter, randomized placebo-controlled trials to have decreased proptosis, diplopia and inflammation after 24 weeks of treatment. This study aims to analyse volumetric and inflammatory changes on orbital imaging prior to and after teprotumumab treatment from one of these trials.DesignRetrospective review.SubjectsSix patients enrolled in the phase III teprotumumab clinical trial (OPTIC, NCT03298867) with active TED who received 24 weeks of teprotumumab and had pre- and post-treatment orbital imaging (CT or MRI). Additionally, 12 non-TED patients (24 orbits) were analysed as a comparative control group.Methods3D volumetric calculations of the extraocular muscles (EOMs), orbital fat, and bony orbit were measured using previously validated image processing software. 3D volumetric results and changes in EOM inflammation were compared with clinical measurements of TED.ResultsTotal EOM volume within each orbit was markedly reduced post-teprotumumab in all patients (n=six patients, 12/12 orbits, pConclusionOrbital imaging demonstrated decreased EOM volumes and orbital fat tissue volumes after teprotumumab treatment.

Kidney disease, especially when it is associated with a reduction in estimated glomerular filtration rate, can be associated with an increase in serum urate (uric acid), suggesting that hyperuricemia in subjects with kidney disease may be a strictly secondary phenomenon. Mendelian randomization studies that evaluate genetic scores regulating serum urate also generally have not found evidence that serum urate is a causal risk factor in chronic kidney disease. Nevertheless, this is countered by a large number of epidemiologic, experimental, and clinical studies that have suggested a potentially important role for uric acid in kidney disease and cardiovascular disease. Here, we review the topic in detail. Overall, the studies strongly suggest that hyperuricemia does have an important pathogenic role that likely is driven by intracellular urate levels. An exception may be the role of extracellular uric acid in atherosclerosis and vascular calcification. One of the more striking findings on reviewing the literature is that the primary benefit of lowering serum urate in subjects with CKD is not by slowing the progression of renal disease, but rather by reducing the incidence of cardiovascular events and mortality. We recommend large-scale clinical trials to determine if there is a benefit in lowering serum urate in hyperuricemic subjects in acute and chronic kidney disease and in the reduction of cardiovascular morbidity and mortality in subjects with end-stage chronic kidney disease.

Objectives Pegloticase rapidly lowers serum urate in uncontrolled/refractory gout patients, with ≥1 tophus resolution in 70% of pegloticase responders and 28% of non-responders. Dual-energy computed tomography (DECT) non-invasively detects MSU deposition, including subclinical deposition, quantifies MSU volumes and depicts bone erosions. This report presents DECT findings in MIRROR open-label trial participants receiving pegloticase+MTX co-therapy. Methods Serial DECT scans were obtained during pegloticase (8 mg biweekly infusions)+oral MTX (15 mg/week) co-therapy. Bilateral hand/wrist, elbow, foot/ankle and knee images were analysed with default post-processing settings. MSU volumes were quantified and bone erosions were identified and evaluated for remodelling (decreased size, sclerosis, new bone formation). DECT and physical examination findings were compared. Results 2 patients underwent serial DECT. Patient 1 (44-year-old male) completed 52 weeks of pegloticase+MTX co-therapy (26 infusions). Baseline examination detected 4 tophus-affected joints while DECT identified 73 MSU-affected joints (total MSU volume: 128.76 cm3). At end-of-treatment, there were no clinically-affected joints and 4 joints with DECT-detected MSU deposition. MSU volume decreased by 99% and bone erosion remodelling was evident. Patient 2 (51-year-old male) had 10 weeks of therapy (5 infusions), discontinuing because of urate-lowering response loss. Baseline examination detected 7 tophus-affected joints while DECT identified 55 MSU-affected joints (total MSU volume: 59.20 cm3). At end-of-treatment, there were 5 clinically affected joints and 42 joints with DECT-detected MSU deposition. MSU volume decreased by 58% and bone erosion remodelling was evident. Conclusion DECT detected subclinical MSU deposition and quantified changes over time. Rapid tophus resolution and bone erosion remodelling occurred during pegloticase+MTX co-therapy. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov, NCT03635957.

Background Pegloticase is a recombinant porcine-like uricase enzyme that is FDA-approved for the treatment of chronic refractory gout in adults. Some patients receiving pegloticase develop anti-drug antibodies, which leads to both loss of pegloticase efficacy and an increased risk for infusion reactions. In the pivotal trials, all patients received pre-infusion medications before each pegloticase dose, including intravenous (IV) hydrocortisone. In clinical practice, many clinicians use methylprednisolone for pre-infusion therapy with pegloticase; however, the efficacy of methylprednisolone compared with hydrocortisone as a pre-infusion medication for pegloticase has not been established. Objective The aim of this study was to compare the efficacy of methylprednisolone versus hydrocortisone as a pre-infusion medication for pegloticase. Methods Data were retrospectively collected from 92 qualifying patients treated with pegloticase and administered pre-infusion prophylaxis with either intravenous hydrocortisone or methylprednisolone. Patient demographics, steroid type and dose, duration of pegloticase therapy, overall number of infusions, and number of infusion reactions were assessed. Results Patients treated with methylprednisolone as a pre-infusion medication received on average 8.5 pegloticase infusions versus 4.9 infusions for patients who were treated with hydrocortisone (p

Background Gout is the most common adult inflammatory arthropathy in the US. Although tophi in the extremities is a known source of the inflammatory cascade, urate deposition in organs throughout the body is not as well recognized. Patients with gout often have associated co-morbidities including renal disease, cardiovascular disease and metabolic syndrome, however, a casual role has not been established. Direct urate deposition in these organ systems may be of interest to link the causality of these systemic disorders. Objectives Perform a literature review including clinical exam, autopsy, pathology, and radiology imaging results demonstrating systemic deposition of urate exclusive of the extremities. Methods PUBMED from 1920 to 2018 was searched to identify reports of non-extremity urate deposition. Key words included: extra-articular gout, systemic deposition of urate, ocular gout, gout nephropathy, renal tophi, gouty heart, cardiac valves and urate, urate deposition in the arteries, prostate and urate, autopsy findings in gout, cutaneous urate deposits, gouty panniculitis, auricular gout, breast and urate, gastrointestinal gout, pancreas and tophus, laryngeal tophus, and spinal gout. The reference lists from these publications were also used to identify additional articles. The literature was reviewed for organ system involvement and documented based on sites of urate deposition within an organ system. Results There were 249 case reports documenting non-extremity urate deposition confirmed by autopsy, biopsy, surgery, clinical exam and/or radiology imaging. Urate deposition was reported in multiple organ systems (Table 1) including the spine, integumentary, ocular, renal, cardiovascular, gastrointestinal, larynx, breast, middle ear, pancreas, nasal, prostate gland, liver, pulmonary, penis, nailbed, and pelvis. Conclusion Numerous case reports document systemic deposition of urate based on autopsy, pathology, imaging and clinical exam. Urate crystal deposition with the formation of tophi and micro-tophi involve multiple organ systems including cardiovascular, renal, spine, integumentary, prostate, bowel, pancreas, eyes, pelvic, breast, lungs, middle ear, larynx, liver, penis, nailbed, and nose. Given the strong association of gout with various comorbidities, this demonstrates a need for further studies to determine the clinical significance of systemic urate deposition with respect to ongoing subclinical inflammation and potential end-organ damage. References [1] Park, J. et al. BMJ Open. 2014; 4:e005308. [2] Nickeleit, V, et al. Nephrol Dial Transplant. 1997; 12:1832-1838. [3] Ao, J, et al. Clinical and Experimental Ophthalmology. 2017; 45: 73–80 [4] Forbess LJ, et al. Semin Arthritis Rheum. 2012; 42:146–54. [5] Elgafy, H, et al. World J Orthop. 2016; 7(11): 766–775. Disclosure of Interests Ada Kumar Shareholder of: I am an employee of Horizon Pharma and own shares in the company., Consultant for: I have worked as a paid consultant for Horizon Pharma., Employee of: I am currently employed by Horizon Pharma., Puja Khanna Grant/research support from: AstraZeneca, SOBI, Ironwood, Horizon, Consultant for: SOBI

Gout, an inflammatory arthritis, affects over nine million people in the US with increasing prevalence. Some medical societies do not recommend treating gout unless it is recurrent. While soft tissue urate deposits (tophi), resultant bone erosions, and joint inflammation are frequently recognized in gout, urate crystal deposits in other sites have been thought to be rare. Recent diagnostic testing, such as dual energy computed tomography (DECT), has led to the recognition that urate deposits are not uncommon in other tissues including the vasculature. To understand the potential risks for untreated gout, we reviewed the literature on extra-articular urate deposition documented by autopsy, histopathology, surgery, and radiology, including the heart, blood vessels, kidney, spine, eye, skin, and gastrointestinal system. These studies extend the significance of gout beyond the rheumatologist and emphasize the need for physicians to follow the American College of Rheumatology guidelines to treat subjects with gout to a goal of achieving serum urate

Background:Gout is the most common inflammatory arthropathy in U.S. adults. Although the severity of this debilitating disease is often defined by the presence of tophi in the joints, systemic deposition of urate in major organ systems including the renal parenchyma is not as well established. Urate is primarily cleared through the kidneys and patients with gout often have concomitant renal disease along with other comorbidities such diabetes, coronary artery disease, and hypertension; however, a causal role between these entities has not yet been carefully established. We hypothesize that urate deposits serve as a trigger in the inflammatory nidus to propogate subclinical tissue damage that results in the chronicity of the disease. This could potentially explain its independent role in the development and progression of chronic kidney disease in gout patients.Objectives:To review the published literature for evidence of urate deposition in the renal parenchyma in patients with gout and summarize the histopathology and imaging findings.Methods:PubMed (from 1940 to 2020) was used to identify reports of autopsy, pathology and radiology imaging demonstrating urate deposition within the native renal parenchyma in patients with gout. Key words included: gout nephropathy, chronic urate nephropathy, renal tophi, gouty kidney, autopsy findings in gout, and renal imaging in gout. The reference lists from these publications were also used to identify additional articles. Literature referencing urate nephrolithiasis and renal transplants were excluded from the study.Results:There were 25 articles documenting renal parenchymal urate deposition in gout patients confirmed by autopsy, biopsy and/or radiology imaging in native kidneys. Among the 19 articles examining urate deposition by autopsy and/or biopsy, 100% found urate deposition in the collecting ducts and adjacent medullary interstitium. Based on these findings, the most commonly proposed mechanism for urate deposition is urate crystal precipitation in the collecting ducts with eventual desquamation of the collecting duct walls from inflammation and/or tubular obstruction with subsequent extrusion of crystals into the medullary interstitium. 89% of reports documented inflammatory cells and/or tubulointerstitial fibrosis adjacent to the renal urate deposits. 68% reported cortical thinning or scarring. In addition, 74% of included publications reported renal vascular pathology including arteriosclerosis, glomerosclerosis and nephrosclerosis. There were 6 imaging articles that all reported abnormal renal ultrasound findings with hyperechogenic renal medullas that were attributed to urate deposition.Conclusion:There is a growing body of literature documenting urate deposition in the renal parenchyma in gout patients based on autopsy, pathology and imaging findings. Inflammation and fibrosis adjacent to regions of urate deposition and vascular changes were common. Given the strong association of gout with renal disease, there is a critical need to elucidate the mechanism by which urate impairs the renal tissue. Thus dedicated investigation is key to determine the prevalence and clinical significance of urate deposition in the kidneys of gout patients.References:[1]Nickeleit, V, et al.Nephrol Dial Transplant.(1997) 12:1832-1838.[2]Tchacarski, V, et al.Intl Urol Nephrol.1992; 24(6): 649-655.[3]Modern, FW.Med Clin North Am.1952;21: 941-51.[4]Linnane, JW, et al.Nephron.1981; 29: 216-22[5]Greenbaum, D, et al. Br Med J. 1961 May 27; 1(5238): 1502–1504[6]Bluestone, R, et al.Seminars in Arthr and Rheum.1977;7(2).[7]Brown, J, et al.NEJM.1950; 243: 325-329.[8]Braga, T., et al.Sci Rep.2017; 7: 39884.Disclosure of Interests: :Puja Khanna Grant/research support from: Dyve, Selecta, Sobi, Consultant of: Sobi, Horizon, Brad Marder Employee of: Horizon Therapeutics, Brian LaMoreaux Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Ada Kumar Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics