Real-World Effectiveness of Pegloticase Associated with Use of Concomitant Immunomodulatory Therapy.

OBJECTIVE: The objective was to ascertain pegloticase persistence and adverse events associated with concomitant immunomodulatory drug use in patients with gout. METHODS: We conducted a retrospective analysis of gout patients using the ACR's Rheumatology Informatics System for Effectiveness (RISE) registry from 1/2016 through 6/2020. The first pegloticase infusion defined the index date. Based on concomitant immunomodulatory drug use, we identified 3 exposure groups: 1) Immunomodulatory drug initiators - patients initiating an immunomodulatory prescription ±60 days from index date; 2) Immunomodulatory drug prevalent users - patients receiving their first immunomodulatory drug prescription >60 days before the index date with at least one prescription within ±60 days of index date; and 3) Immunomodulatory non-users - patients receiving pegloticase without concomitant IMM drugs. We calculated the proportion of patients achieving a serum urate (SU) ≤6mg/dL and with lab abnormalities (WBC <3.4; platelets <135,000; HCT <30; ALT or AST ≥1.5X ULN) within 180 days after the index date. Cox regression analyzed time to pegloticase discontinuation controlling for potential confounders. RESULTS: We identified 700 pegloticase users (91 immunomodulatory drug initiators, 33 immunomodulatory drug prevalent users, and 576 non-users) with median follow-up of 14 months. Immunomodulatory drug users were less likely to discontinue pegloticase. The adjusted hazard ratio of pegloticase discontinuation associated with concomitant immunomodulatory drug initiation was 0.52 (95% CI: 0.37,0.75) and 0.69 (95% CI: 0.42,1.16) for prevalent users. Lab abnormalities were uncommon (<5%) and were not higher with concomitant immunomodulatory use. CONCLUSION: Consistent with clinical trials, results from this large observational registry suggest that concomitant immunomodulatory drug use improves pegloticase persistence.

The safety of glucocorticoids in the treatment of inflammatory rheumatic disease: new evidence.

PURPOSE OF REVIEW: Glucocorticoids justifiably remain a cornerstone in the treatment of many inflammatory rheumatic diseases but many are opposed to their use because of the side effects, most of them known to be dose-dependent. Most concerns regarding glucocorticoids stem from observational studies which are affected by several forms of bias, mainly confounding by indication, that may result in overestimation of harm. Solid evidence regarding the safety of low-dose glucocorticoids remains remarkably scarce. RECENT FINDINGS: Several observational studies showed heterogeneous results and two 6-month trials showed no increase of harm. The GLORIA trial of 5 mg/day prednisolone vs. placebo in patients aged 65+ is the first randomized control trial with glucocorticoids safety as coprimary outcome. The benefits of glucocorticoids in terms of symptoms and structural damage were confirmed, but the proportion of patients with at least one adverse event of special interest (serious or glucocorticoids-related) was increased by 24%, mostly due to nonsevere infections. SUMMARY: Based on current evidence the benefit-risk balance of low-dose glucocorticoids in rheumatoid arthritis, and probably in other rheumatic diseases is generally favourable. Physicians should be aware of the risks and mitigate them, but avoid the negative effects of unfounded fear.

Designing a Strategy Trial for the Management of Gout: The Use of a Modified Delphi Panel.

OBJECTIVE: Disagreement exists between rheumatology and primary care societies regarding gout management. This paper describes a formal process for gathering input from stakeholders in the planning of a trial to compare gout management strategies. METHODS: We recruited patients, nurses, physician assistants, primary care clinicians, and rheumatologists to participate in a modified Delphi panel (mDP) to provide input on design of a trial focused on optimal management for primary care patients with gout. The 16 panelists received a plain-language briefing document that discussed the rationale for the trial, key clinical issues in gout, and aspects of trial design. The panelists also received information and considerations on nine voting questions (VQs), judged to be the key design questions. Cognitive interviews with panelists ensured that the VQs were understood by the range of panelists involved in the mDP. Panelists were asked to score all VQs from 1 (definitely no) to 9 (definitely yes). Two voting rounds were conducted-round 1 by email and round 2 by video conference. RESULTS: The VQs were modified through the cognitive interviews. The round 1 voting resulted in consensus on eight items, with consensus defined as median voting score in the same tercile (1-3, 4-6 or 7-9). Re-voting at the meeting (round 2) reached consensus on the remaining item. CONCLUSION: An mDP with various stakeholders facilitated consensus on the design of a trial of different management strategies for chronic gout. This method may be useful for designing trials of clinical questions with substantial disagreement across stakeholders.

Reduction of Hip and Other Fractures in Patients Receiving Teriparatide in Real-World Clinical Practice: Integrated Analysis of Four Prospective Observational Studies.

The phase 3 teriparatide Fracture Prevention Trial showed significant reductions in vertebral (VF) and nonvertebral (NVF) fractures; however, patient exposure was insufficient for full analysis of low-incidence fractures, including hip. We assessed fracture results in pooled data from four prospective, observational teriparatide studies. Ambulatory women and men with osteoporosis received subcutaneous teriparatide 20 µg/day for up to 24 months per routine clinical practice. Fracture rates were compared between 6-month periods, using 0 to 6 months of treatment as the reference period. Analyses used a piecewise exponential model for first fracture. Hip, NVF, clinical VF (CVF), any clinical, and wrist fractures were assessed. For 8828 patients analyzed, mean age was 71 years; mean (SD) treatment duration was 17.4 (8.6) months. The rate of hip fracture decreased significantly for the > 12 to 18-month (- 47.7%) and > 18-month periods (-85.2%) versus the first 6 months of therapy, and for the > 18 versus the > 6 to 12-month period. NVF, CVF, and all clinical fractures were all significantly decreased in each post-reference period, with maximum decreases (> 18-month period) of 52.7%, 69.4%, and 61.2%, respectively, versus 0 to 6 months. No significant reduction was seen for rates of wrist fracture. Teriparatide treatment was associated with statistically significant decreases in hip fracture rate, particularly for > 18 months of treatment, and in NVF, CVF, and all clinical fracture rate in real-world patients. These results should be interpreted in the context of the non-controlled design of the source studies.

Real-world effectiveness of teriparatide on fracture reduction in patients with osteoporosis and comorbidities or risk factors for fractures: Integrated analysis of 4 prospective observational studies.

INTRODUCTION: Teriparatide significantly reduces fracture rates in clinical trials; however, those study populations were relatively restricted and included too few patients to analyze fracture outcomes within clinically important patient subgroups. We assessed fracture outcomes in subgroups of osteoporosis patients from 4 real-world teriparatide observational studies. METHODS: Patients received teriparatide 20 µg/day for up to 24 months. Fracture rates were compared between 0 to 6 months versus >6 months using a piecewise exponential model for first fracture. Analyses included incident clinical vertebral fractures (CVF) and nonvertebral fractures (NVF), and clinical fractures (CVF and NVF) by subgroups of gender, age <75 or ≥75 years, diabetes, prior bisphosphonates use, rheumatoid arthritis (RA), glucocorticoid use, prior hip, and prior vertebral fracture. RESULTS: The population included 8828 patients (8117 women, 92%) with mean (SD) age 71 (10.6) years and teriparatide treatment duration 17.4 (8.6) months. Overall, CVF, NVF, clinical fracture, and hip fracture rates decreased by 62%, 43%, 50%, and 56%, respectively (all p < .005) for >6 months versus 0 to 6 months. Subgroup analyses all showed significantly decreased rates after >6 months except for NVF reduction in males (n = 710, fracture rate low during months 0 to 6) and in patients using glucocorticoids, and CVF in patients with prior hip fracture. The effects of teriparatide on CVF, NVF, and clinical fractures over time were statistically consistent in all subgroups except age for CVF (p = .074, patients <75 years of age responded better), and diabetes for clinical fractures (p = .046, patients with diabetes responded better), although all of these subgroups experienced significant reductions over time. Glucocorticoids, prior bisphosphonate, and prior vertebral fracture were associated with increased CVF, NVF, and clinical fracture rates; RA, prior hip fracture and female gender were associated with higher NVF and clinical fracture rates; increased age was associated with higher CVF and clinical fracture rates. CONCLUSIONS: Data from 4 real-world observational studies showed statistically significant reductions during teriparatide treatment in rates of CVF, NVF, and clinical fractures in clinically relevant patient subgroups. These results should be interpreted in the context of the non-controlled design of the source studies.

Which fractures are most attributable to osteoporosis?

BACKGROUND: Determining anatomic sites and circumstances under which a fracture may be a consequence of osteoporosis is a topic of ongoing debate and controversy that is important to both clinicians and researchers. METHODS: We conducted a systematic literature review and generated an evidence report on fracture risk based on specific anatomic bone sites and fracture diagnosis codes. Using the Research and Development/University of California at Los Angeles appropriateness process, we convened a multidisciplinary panel of 11 experts who rated fractures according to their likelihood of being because of osteoporosis based on the evidence report. Fracture sites (as determined by International Classification of Diseases Clinical Modification codes) were stratified by four clinical risk factor categories based on age, sex, race/ethnicity (African American and Caucasian), and presence or absence of trauma. RESULTS: Consistent with current clinical experience, the fractures rated most likely because of osteoporosis were the femoral neck, pathologic fractures of the vertebrae, and lumbar and thoracic vertebral fractures. The fractures rated least likely because of osteoporosis were open proximal humerus fractures, skull, and facial bones. The expert panel rated open fractures of the arm (except proximal humerus) and fractures of the tibia/fibula, patella, ribs, and sacrum as being highly likely because of osteoporosis in older Caucasian women but a lower likelihood in younger African American men. CONCLUSION: Osteoporosis attribution scores for all fracture sites were determined by a multidisciplinary expert panel to provide an evidence-based continuum of the likelihood of a fracture being associated with osteoporosis.

How to ascertain drug safety in the context of benefit. Controversies and concerns.

There is great concern about clearly defining benefit and risk in the context of both drug development and clinical practice. In view of this pressure, the OMERACT Executive identified the need to bring together clinical trialists, pharmacoepidemiologists, clinicians, clinical epidemiologists, statistical experts, and regulatory representatives to discuss different approaches to define risk and perhaps improved ways to express it. Each attendee spoke on a given topic and the group was charged to consider the issue of risk in the context of formally posed questions. This article provides a summary of the presentations and outlines the discussions that followed.