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To assess efficacy, safety, pharmacokinetics, and immunogenicity of pegloticase plus methotrexate (MTX) versus pegloticase plus placebo cotreatment for uncontrolled gout in a randomized, placebo-controlled, double-blind trial.This study included adults with uncontrolled gout, defined as serum urate ≥7 mg/dl, oral urate-lowering therapy failure or intolerance, and presence of ongoing gout symptoms including ≥1 tophus, ≥2 flares in the past 12 months, or gouty arthritis. Key exclusion criteria included MTX contraindication, current immunosuppressant use, G6PDH deficiency, and estimated glomerular filtration rate40 ml/minute/1.73 mA total of 152 patients were randomized, 100 to receive pegloticase plus MTX, 52 to receive pegloticase plus placebo. Significantly higher treatment response occurred during month 6 in the MTX group versus the placebo group (71.0% [71 of 100 patients] versus 38.5% [20 of 52 patients], respectively; between-group difference 32.3% [95% confidence interval 16.3%, 48.3%]) (P 0.0001 for between-group difference). During the first 6 months of pegloticase plus MTX or pegloticase plus placebo treatment, 78 (81.3%) of 96 MTX patients versus 47 (95.9%) of 49 placebo patients experienced ≥1 adverse event (AE), most commonly gout flare (64 [66.7%] of 96 MTX patients and 34 [69.4%] of 49 placebo patients). Reports of AEs and serious AEs were comparable between groups, but the infusion reaction rate was considerably lower with MTX cotherapy (4.2% [4 of 96 MTX patients, including 1 patient who had anaphylaxis]) than with placebo cotherapy (30.6% [15 of 49 placebo patients, 0 who had anaphylaxis]) (P 0.001). Antidrug antibody positivity was also lower in the MTX group.MTX cotherapy markedly increased pegloticase response rate over placebo (71.0% versus 38.5%) during month 6 with no new safety signals. These findings verify higher treatment response rate, lower infusion reaction incidence, and lower immunogenicity when pegloticase is coadministered with MTX.

Background/Objective Pegloticase is used for treatment of refractory gout, which has failed maximal medical management, but only 42% of patients respond completely to treatment because of the presumed development of antidrug antibodies, which rapidly clear the pegloticase molecule. Immunomodulatory medications temper antidrug antibody development in other diseases. The aim of this case series was to investigate the utility of adding methotrexate to a pegloticase regimen to increase the response durability in a real-world practice setting. Methods In this multicenter, proof-of-concept, observational case series, refractory tophaceous gouty arthropathy patients being started on pegloticase 8 mg every 2 weeks were identified. The patients began oral methotrexate 15 mg/wk and folic acid 1 mg/d, 1 month prior to the initial pegloticase administration, and continued throughout pegloticase treatment. Responders were defined by demonstrating ≥80% of preinfusion serum uric acid (sUA) levels

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.

Purpose of Review Gout is a systemic disease from which some patients develop numerous painful tophi that adversely affect quality of life and functionality. Some patients treated with oral urate-lowering therapy are unable to maintain serum urate levels below 6 mg/dL, and these patients, thus classified as having refractory or uncontrolled gout, often require therapy with pegloticase to reduce symptoms and tophaceous burden. The objective of this expert opinion review is to summarize the available evidence supporting the use of concomitant immunomodulators with pegloticase to prevent development of anti-drug antibodies (ADAs) when treating patients with uncontrolled gout. Recent Findings Emerging evidence suggests that adding an immunomodulator to pegloticase therapy can substantially increase response rates to double those observed in phase 3 randomized controlled trials. Summary The combination of immunomodulation with pegloticase should be considered in routine clinical practice to improve durability of response, efficacy, and safety among patients with uncontrolled gout who otherwise have limited therapeutic options.

Background: Publications suggest immunomodulation co-therapy improves responder rates in uncontrolled/refractory gout patients undergoing pegloticase treatment. The MIRROR open-label trial showed a 6-month pegloticase+methotrexate co-therapy responder rate of 79%, compared to an established 42% pegloticase monotherapy responder rate. Longer-term efficacy/safety data are presented here.Methods: Uncontrolled gout patients (serum urate [SU]≥6 mg/dL and SU≥6 mg/dL despite urate-lowering therapy [ULT], ULT intolerance, or functionally-limiting tophi) were included. Patients with immunocompromised status, G6PD deficiency, severe kidney disease, or methotrexate contraindication were excluded. Oral methotrexate (15 mg/week) and folic acid (1 mg/day) were administered 4-weeks before and during pegloticase therapy. Twelve-month responder rate (SUResults: Fourteen patients were included (all male, 49.3 ± 8.7 years, 13.8 ± 7.4 year gout history, pre-therapy SU: 9.2 ± 2.5 mg/dL). Three patients were non-responders and discontinued study treatment before 24-weeks, one patient exited the study per-protocol at 24-weeks (enrolled prior to treatment extension amendment), and 10 remained in study through Week 52. Of the 10, 8 completed 52-weeks of pegloticase+methotrexate and were 12-month responders. The remaining two discontinued pegloticase+methotrexate at Week 24 (met treatment goals) and stayed in study under observation (allopurinol prescribed at physicians’ discretion); one remained a responder at 12-months. At 52-weeks, change from baseline in SU was -8.2 ± 4.1 mg/dL (SU: 1.1 ± 2.4 mg/dL, n=10). Gout flares were common early in treatment but progressively decreased while on therapy (Weeks 1-12: 13/14 [92.9%], Weeks 36-52: 2/8 [25.0%]). One patient recovered from sepsis (serious AE). Two non-responders developed high ADA titres; fewer patients had trough concentrations (Cmin) below quantitation limit (BQL) and median Cmin was higher (1.03 mg/mL vs. BQL) than in pegloticase monotherapy trials.Conclusions: Methotrexate+pegloticase co-therapy was well-tolerated over 12-months, with sustained SU lowering, progressive gout flare reduction, and no new safety concerns. Antibody/PK findings suggest methotrexate attenuates ADA formation, coincident with higher treatment response rates.Trial registration: ClinicalTrials.gov: NCT03635957, registered 17 August 2018, https://clinicaltrials.gov/ct2/show/NCT03635957

Introduction Pegloticase is a recombinant PEGylated uricase that converts relatively insoluble urate to highly water-soluble allantoin, which is readily excreted by the kidneys. It is the first and only biologic treatment indicated for refractory or uncontrolled gout. Clinical trials showed a 6-month pegloticase responder rate of 42%, with the non-responder rate largely being attributed to the development of high-titer anti-drug antibodies (ADAs) against pegloticase. Immunomodulation attenuates ADA formation to biologics in a number of autoimmune conditions, but their use with pegloticase for uncontrolled gout is less established. This systematic review examined published cases of refractory gout patients treated with immunomodulation in combination with pegloticase. Methods Published cases of immunomodulation with pegloticase were identified in a PubMed search and in abstract databases of major rheumatology society meetings (2012–2020). Duplicate and review articles were excluded, as were those that did not include cases of pegloticase use with immunomodulation. Cases with off-label pegloticase administration schedules were also excluded. Pegloticase response was defined according to each study's specified standard. Results Ten publications describing 82 cases of pegloticase use in the setting of immunomodulation were identified. Overall pegloticase response rate was 82.9%. Patients co-treated with an individual immunomodulator had the following response rates: methotrexate: 87.5% (35 of 40 patients), mycophenolate mofetil: 86.4% (19 of 22 patients vs. pegloticase monotherapy [placebo]: 40% [4 of 10 patients]), azathioprine: 63.6% (7 of 11 patients), and leflunomide: 66.7% (4 of 6 patients). A single patient was co-treated with cyclosporin and was a responder. The two patients treated with more than one immunomodulator were both responders. Conclusion Published reports suggest that immunomodulation co-therapy has the potential to markedly improve pegloticase responder rates in patients with uncontrolled gout.

ObjectiveTo examine the efficacy and safety of pegloticase in combination with methotrexate (MTX) in patients with uncontrolled gout in an exploratory, open-label clinical trial (ClinicalTrials.gov: NCT03635957) prior to a randomized, controlled trial.MethodsA multicenter, open-label efficacy and safety study of pegloticase with MTX co-treatment was conducted in patients with uncontrolled gout. Patients were administered oral MTX (15 mg/week) and folic acid (1 mg/day) 4 weeks prior to and throughout pegloticase treatment. The primary study outcome was the proportion of responders, defined as serum uric acid (sUA) < 6 mg/dL for ≥ 80% of the time during Month 6 (Weeks 20, 22, and 24). All analyses were performed on a modified intent-to-treat population, defined as patients who received ≥ 1 pegloticase infusion.ResultsSeventeen patients were screened and 14 patients (all men, average age 49.3 ± 8.7 years) were enrolled. On Day 1, mean sUA was 9.2 ± 2.5 mg/dL, and 12 of the 14 patients had visible tophi. At the 6-month timepoint, 11/14 (78.6%, 95% CI 49.2–95.3%) met the responder definition, with 3 patients discontinuing after meeting protocol-defined treatment discontinuation rules (preinfusion sUA values > 6 mg/dL at 2 consecutive scheduled visits). All patients tolerated MTX. No new safety concerns were identified.ConclusionIn this study, an increased proportion of patients maintained therapeutic response at 6 months when treated concomitantly with MTX and pegloticase as compared to the previously reported 42% using pegloticase alone. These results support the need for a randomized study of MTX or placebo with pegloticase to validate these open-label findings.

Pegloticase is a highly effective treatment for refractory gouty arthropathy. Unfortunately, the medication is also highly immunogenic, leading to infusion reactions, loss of drug efficacy and anaphylaxis. Desensitisation, a procedure to tolerise a patient to a medication previously causing a hypersensitivity reaction, has been used successfully in oncology for chemotherapy treatment. The same principle can be applied to other specialties. Presented is a 48-year-old man who experienced multiple, severe infusion reactions to pegloticase administered for gouty arthropathy. A rapid desensitisation was performed using an outpatient, 3-bag, 12-step protocol, which allowed multiple additional pegloticase infusions to be performed without incident. This is the first reported case of a patient successfully desensitised after an infusion reaction to pegloticase. Though additional patients are needed to confirm these results, this represents a significant opportunity to recapture and continue pegloticase therapy in patients treated for refractory gouty arthropathy.

Background Pegloticase is a recombinant DNA-produced porcine-like uricase enzyme, which metabolizes relatively insoluble urate to highly soluble allantoin. It is used in the treatment of refractory gout which has failed maximal medical management, typically with xanthine oxidase inhibitors (XOI). Studies have shown a complete responder rate of 42% when defined as repeat serum uric acid (sUA) levels 80% of the time during months 3 and 6 of treatment. Patients that do not maintain a low uric acid while on pegloticase therapy are presumed to have developed anti-drug antibodies (ADA) which rapidly clear the pegloticase molecule. As is routinely utilized in the treatment of other rheumatologic diseases, coadministration of immunomodulatory medications, such as methotrexate, could potentially temper the development of these ADAs (as defined by maintenance of sUA response) in patients treated with pegloticase for refractory gouty arthropathy. Objectives The aim of the current case series was to identify and clinically evaluate patients in a real-world practice setting in order to investigate the utility of adding methotrexate to a pegloticase regimen to increase the durability of response. Methods In this prospective, proof-of-concept, observational case series, 10 sequential patients with refractory tophaceous gouty arthropathy being started on treatment with pegloticase 8 mg every two weeks (as per the label) were identified from 3 separate infusion centers. No inclusion/exclusion criteria were implemented or prescreening performed. Methotrexate (MTX) 15 mg orally once weekly and folic acid 1 mg orally once daily was started one month prior to the initial administration of pegloticase and continued throughout pegloticase treatment. Any infusion pre-medications, which were consistent with standard practices, were administered per the individual physician’s discretion as well as management of any gout flares which occurred during the treatment course. As per standard of care, sUA was measured every two weeks, prior to each subsequent infusion. At the completion of pegloticase treatment for all patients, the number and percentage of patients able to maintain an sUA at goal Results Ten patients ranging in age from 35-80 were identified, from 3 separate infusion centers. There were 143 total pegloticase infusions performed within the observation period. All 10 patients received at least 10 infusions (5 months), 9 patients at least 12 infusions (6 months), 5 patients at least 16 infusions (8 months), 2 patients at least 18 infusions (9 months), and 1 patient received 19 infusions. All 10 patients completed a full course of pegloticase treatment. All patients stayed on MTX 15 mg/week. There were no dose adjustments. 100% of patients were responders as defined by >80% of sUA levels being maintained at goal Conclusion In this proof-of-concept case series of 10 sequential patients, pretreatment and co-administration of methotrexate 15 mg orally once weekly and folic acid 1 mg orally once daily with pegloticase resulted in a 100% maintenance of pegloticase sUA response with no infusion reactions. Although additional studies would be needed to corroborate these results, these data support a potential paradigm shift in treatment of refractory gout with pegloticase. Reference [1] Sundy JS, et al. JAMA. 2011;306:711 Acknowledgement Research sponsored by the Alaska Rheumatology Alliance. Disclosure of Interests John Botson Shareholder of: Publicly traded stock: Horizon, Johnson and Johnson, Pfizer, Rigel, Consultant for: Celgene, Eli Lilly, Genentech, Horizon, Mallinckrodt, Novartis, Pfizer, Speakers bureau: Celgene, Eli Lilly, Horizon, Mallinckrodt, Novartis, Pfizer, Jeff Peterson Consultant for: Celgene, Genentech, Horizon, Lilly, Novartis, Regeneron (2017-2018), Speakers bureau: Abbvie, Horizon, Lilly, Novartis (2017-2018)

Background:Gout development follows persistent serum uric acid (sUA) elevation. Patients who are refractory to or cannot tolerate oral urate lowering therapies (ULTs) have limited treatment options. Pegloticase is effective in treating refractory gout, but many patients develop anti-drug antibodies (ADAs), which are associated with loss of urate-lowering efficacy1-3 and infusion reactions (IRs).1,2 In phase 3 trials, the pooled pegloticase responder rate during Months 3 and 6 combined was 42% (8 mg infusion every 2 weeks), with high-titer ADA positive patients losing efficacy prior to 6 months.1 The 6-month results from the MIRROR open-label trial (79% response rate [11/14], 95%CI 49-95%)4 suggest that methotrexate (MTX) administered in conjunction with pegloticase increases treatment responder rate.Objectives:To examine longer-term (12-month) exploratory endpoints from the MIRROR open-label trial, including joint, overall health, and gout global assessments. Serial dual-energy computed tomography (DECT) images were also examined when available.Methods:Adult patients with uncontrolled gout (sUA ≥6 mg/dL with ≥1 of the following: sUA ≥6 mg/dL despite ULT use, intolerance to ULT, or functionally limiting tophaceous deposits) were included. Patients with immunocompromised status, G6PD deficiency, severe renal impairment, or MTX contraindication were excluded. Patients were administered oral MTX (15 mg/week) and folic acid (1 mg/day) 4 weeks prior to and throughout pegloticase therapy (8 mg biweekly infusion for up to 52 weeks). Exploratory outcomes included mean change from baseline (CFB) in number of affected joints (tophi, swollen, tender), Health Assessment Questionnaire (HAQ) scores (Disability Index [DI; score 0−3], Pain [score 0−100], Health [score 0−100]), and Gout Global Assessments (Patient, Physician; score 0−10). A decrease in these measures reflects clinical/patient-reported health improvement. Change in urate deposition volume, as measured on DECT imaging, was also examined as available. Analyses were performed on the modified intent-to-treat (mITT) population (≥1 pegloticase infusion received).Results:14 patients (all male, mean±SD age: 49.3±8.7 years) made up the mITT population. Mean±SD sUA prior to pegloticase treatment was 9.2±2.5 mg/dL and 13 patients had visible tophi. 3 patients discontinued due to 2 consecutive sUA levels >6 mg/dL and 1 patient completed the study at week 24 (pre-protocol amendment extending treatment from 24 to 52 weeks). 10 patients completed the 52-week study. Of these, 8 patients received 26 infusions and 2 patients received 12 infusions, discontinued pegloticase after meeting their treatment goal at 24 weeks, and started allopurinol while remaining in study under observation. At week 52 (n=10, sUA=1.1±2.5 mg/dL), the number of affected joints improved, along with HAQ measures (Figure 1). Global Assessments of Gout also improved (Physician: CFB=-5.7±2.6, Patient CFB=-4.6±2.1) and majority of subjects had a score of 0 or 1 (0=“excellent health”) at week 52 (Physician: 0.3±0.5, Patient: 1.1±1.3). Two patients had available DECT imaging. One received pegloticase/methotrexate co-therapy thru week 52 and had a marked reduction in total urate volume (baseline: 128.76 cm3, week 52: 1.33 cm3). The other received only 5 pegloticase infusions, but also showed total urate volume reduction (baseline: 59.20 cm3, week 10: 25.07 cm3). Both patients displayed improvement in bone erosion healing.Conclusion:These 12-month exploratory endpoints of the MIRROR open-label trial suggest that MTX/pegloticase co-therapy results in meaningful changes in clinical evaluations (tophaceous, tender, and swollen joint counts), and patient-reported outcomes (pain, disability) in patients with uncontrolled gout.References:[1]Sundy JS et al. JAMA 2011;306:711-20[2]Baraf HS et al. J Clin Rheumatol 2014;20:427-32[3]Lipsky PE et al. Arthritis Res Ther 2014, 16:R60[4]Botson JK et al. J Rheum 2020 [Epub ahead of print]Disclosure of Interests:John Botson Speakers bureau: Horizon Therapeutics, Celgene, Novartis, and AbbVie, Consultant of: Horizon Therapeutics, Celgene, Novartis, and AbbVie, Grant/research support from: Horizon Therapeutics and Radius Health, Paul M. Peloso Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Katie Obermeyer Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Brian LaMoreaux Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Lin Zhao Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Michael E. Weinblatt Shareholder of: Lycera, Can-Fite BioPharma, Scipher Medicine, Inmedix, and Vorso, Consultant of: Bristol Myers Squibb, Corona, Lilly, AbbVie, Amgen, Arena, GlaxoSmithKline, Gilead Sciences, Horizon Therapeutics, Lycera, Novartis, Pfizer, Roche, Samsung, Scipher Medicine, and Set Point, Grant/research support from: Amgen, Bristol-Myers Squibb, Crescendo Bioscience, Lilly and Sanofi, Jeff Peterson Speakers bureau: Horizon Therapeutics plc, Grant/research support from: Horizon Therapeutics plc.

Background:Gout is a painful inflammatory arthritis caused by persistently elevated serum uric acid (sUA) levels. Pegloticase, an infused recombinant PEGylated uricase, rapidly lowers sUA levels by converting uric acid to allantoin, a water-soluble molecule that is readily excreted by the kidneys. In the phase 3 clinical trials, 42% of patients1dosed with pegloticase every two weeks maintained sUA levels below 6.0 mg/dL during months 3 and 6 of pegloticase treatment. The loss of pegloticase efficacy has been attributed to the development of anti-drug antibodies (ADAs)1-3and these ADAs have been associated with infusion reactions (IRs).1,2Case reports4and prospective case series5, 6indicate that methotrexate (MTX) may allow patients to attain more complete therapeutic benefits, presumably through attenuation of pegloticase immunogenicity. The current study prospectively examines the efficacy and safety of MTX-pegloticase co-therapy in patients with uncontrolled gout.Objectives:To assess efficacy and safety of concomitant pegloticase and MTX therapy in patients with uncontrolled gout.Methods:Adult patients with uncontrolled gout who were beginning pegloticase therapy were considered for enrollment in this ongoing multicenter, open-label, efficacy and safety study of pegloticase with MTX co-treatment (NCT03635957). Patients were administered oral MTX (15 mg/week) and folate (1 mg/day) 4 weeks prior to the first pegloticase infusion (Day 1) and throughout the pegloticase treatment period. Blood was drawn prior to each infusion to measure sUA level, monitor clinical parameters, and examine for ADA development. All patients followed typical IR prophylaxis protocols (fexofenadine one day before and the morning of each infusion and acetaminophen and IV corticosteroid the morning of each infusion). Patients also received gout flare prophylaxis with either NSAIDs, colchicine or prednisone initiated at least 1 week prior to Day 1. The primary study outcome was the proportion of responders, defined as sUA Results:A total of 17 patients were screened and 14 patients (all men, average age: 49.3 ± 8.7 years) were enrolled. On Day 1, mean sUA was 9.2 ± 2.5 mg/dL and 12 of the 14 patients had visible tophi. At the 6 months timepoint, 11/14 (78.6%, 95%CI 49.2-95.3%) met the responder definition, with 3 patients discontinuing after meeting stopping rules (pre-infusion sUA values greater than 6 mg/dL at 2 consecutive scheduled visits). All patients tolerated MTX. One serious AE of bacterial sepsis occurred (resolved). AEs that occurred in >1 patient during the co-treatment period were: diarrhea and upper respiratory tract infection in 3 patients each, sinusitis, muscle strain, and hypertension in 2 patients each. Gout flares occurred in 12/14 (85.7%) patients. No new safety concerns were identified.Conclusion:An increased proportion of patients maintained therapeutic response at 6 months when treated concomitantly with MTX and pegloticase (78.6%) when compared to the previously reported 42% using pegloticase alone.1These results support and reflect the improved response rates demonstrated in two prior case series.5,6A definitive randomized double-blinded trial evaluating pegloticase with MTX vs. pegloticase with placebo is ongoing.References:[1]Sundy JS et al.JAMA2011;306:711-20.[2]Baraf HS et al.J Clin Rheumatol2014;20:427-32.[3]Lipsky PE et al.Arthritis Res Ther2014;16:R60.[4]Bessen SY et al.Semin Arthritis Rheum2019;49:56-61.[5]Botson J, Peterson J.Ann Rheum Dis2019;78:A1289.[6]Albert JA et al.Arthritis & Rheumatology2019;71(S10):A1236.Disclosure of Interests: :John Botson Grant/research support from: Horizon Therapeutics (PI and study site), Radius Health (study site), Consultant of: Horizon Therapeutics, Speakers bureau: Celgene, Eli Lilly, Horizon Therapeutics, Mallinckrodt, Novartis, Pfizer, Paul M. Peloso Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Katie Obermeyer Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Brian LaMoreaux Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Michael E. Weinblatt Grant/research support from: BMS, Amgen, Lilly, Crescendo and Sonofi-Regeneron, Consultant of: Horizon Therapeutics, Bristol-Myers Squibb, Amgen, Abbvie, Crescendo, Lilly, Pfizer, Roche, Gilead, Jeff Peterson Grant/research support from: Abbvie, UCB, Smith Klein, Horizon Therapeutics, Consultant of: Lilly, Norvartis, Horizon Therapeutics, Speakers bureau: Lilly, Novartis, Horizon Therapeutics, Abbvie, Genentech