Faculty Bibliography

OBJECTIVES:The objective of this systematic review was to assess the effects of interleukin-1β (IL-1β) inhibitors on gout flares. METHODS:Studies published between 2011 and 2022 that evaluated the effects of IL-1β inhibitors in adult patients experiencing gout flares were eligible for inclusion. Outcomes including pain, frequency and intensity of gout flares, inflammation, and safety were assessed. Five electronic databases (Pubmed/Medline, Embase, Biosis/Ovid, Web of Science and Cochrane Library) were searched. Two independent reviewers performed study screening, data extraction and risk of bias assessments (Cochrane Risk of Bias Tool 2 for randomised controlled trials [RCTs] and Downs and Black for non-RCTs). Data are reported as a narrative synthesis. RESULTS:Fourteen studies (10 RCTs) met the inclusion criteria, with canakinumab, anakinra, and rilonacept being the three included IL-1β inhibitors. A total of 4367 patients with a history of gout were included from the 14 studies (N = 3446, RCTs; N = 159, retrospective studies [with a history of gout]; N = 762, post hoc analysis [with a history of gout]). In the RCTs, canakinumab and rilonacept were reported to have a better response compared to an active comparator for resolving pain, while anakinra appeared to be not inferior to an active comparator for resolving pain. Furthermore, canakinumab and rilonacept reduced the frequency of gout flares compared to the comparators. All three medications were mostly well-tolerated compared to their comparators. CONCLUSION:IL-1β inhibitors may be a beneficial and safe medication for patients experiencing gout flares for whom current standard therapies are unsuitable. REVIEW PROTOCOL REGISTRATION:PROSPERO ID: CRD42021267670.

PURPOSE OF REVIEW/OBJECTIVE:To discuss what is currently known about the association and potential mechanistic interactions of hyperuricemia and gout with peripheral arterial disease (PAD). RECENT FINDINGS/RESULTS:Gout patients are at increased risk for coronary artery disease, but less is known about their risk for PAD. Studies suggest that the presence of gout and hyperuricemia are associated with PAD independent of known established risk factors. Moreover, higher SU was found to be associated with greater odds of having PAD and was independently associated with decreased absolute claudication distance. Urate's role in free radical formation, platelet aggregation, vascular smooth muscle proliferation, and impaired endothelial vasodilation may promote atherosclerotic progression. Studies suggest that patients with hyperuricemia or gout are at higher risk for developing PAD. Evidence is stronger for the relationship between elevated SU and PAD than for gout and PAD, but more data is needed. Whether elevated SU serves as a marker or cause of PAD remains to be investigated.

Background/Purpose: Knee osteoarthritis (OA) is an inflammatory disease, with a probable role for IL-1b. Calcium and urate crystals may promote OA by activating the NLRP3 inflammasome to produce IL-1b. Colchicine is a well-tolerated anti-inflammatory agent that inhibits the inflammasome and suppresses IL-1b. Studies examining the impact of colchicine on knee OA have yielded varying results, with some reporting pain relief, others improvement of inflammatory markers, and none assessing synovial effusions. We report the interim, blinded results of our ongoing colchicine trial for knee OA.
Method(s): CLOAK is a randomized, double-blind, placebo-controlled trial of colchicine (once daily for 3 months) (Figure 1). We are enrolling subjects >= 40 years of age, with symptomatic knee OA, Kellgren-Lawrence grade 2 or 3 radiographs, and willingness to forego other anti-inflammatory therapy during the trial. The primary outcome is the change in knee pain by visual analog scale (VAS) after 3 months of treatment, comparing the colchicine and placebo groups. Secondary outcomes include pre to post treatment Knee Injury and Osteoarthritis Outcome Score (KOOS), mean doses of analgesics used, and changes in plasma and peripheral blood leukocyte inflammatory markers. Patients undergo knee ultrasound (US) pre-and post-treatment to assess synovitis and effusion. We aspirate synovial fluid when appropriate, and will analyze all available blood and synovial samples after study completion.
Result(s): To date, 715 potential subjects have been contacted, 82 screened, and 71 enrolled. Among 60 who have completed the study, 51.6% are male, 60% White, 30% Black, 3.3% Asian and 6.7% other, with mean BMI of 27.6 kg/m2 and age of 66.8 years. The mean VAS pain score among all completing participants (subjects and controls combined) improved Figure 1. Flow diagram of study plan. Figure 2. Subject improvement in KOOS score from beginning to end of study, according to high or low baseline severity as measured by VAS and KOOS scores and presence of synovial effusion. by 0.98 units in the index knee, and mean KOOS scores improved for symptoms, pain, activities of daily living (ADL), sports activity, and quality of life (QOL). Overall 36 (60%) demonstrated VAS improvement (mean improvement 2.3) whereas 24 (40%) demonstrated no change or worsening. Overall, subjects whose VAS improved showed concordant improvement in the KOOS: mean symptoms by 10.5, pain by 12.4, ADL by 14.8, sports activity by 5.8 and QOL by 11.4 units. The subsets of patients with baseline VAS >=6 and baseline KOOS <=60 (i.e., more severe) showed significantly more 3-month KOOS pain improvement, even with the blinded inclusion of placebo (Figure 2). All underwent US at baseline and 3 months. Among 36 patients with VAS improvement over 3 months, 6 had baseline synovial effusions >=4 mm (in longitudinal and transverse views) and 5 of these effusions were smaller on US post-treatment and one remained stable.
Conclusion(s): The results of this blinded analysis are consistent with a potential benefit of colchicine for pain, function and effusion in subjects not taking other anti-inflammatory agents. Enrollment is ongoing and the study will be unblinded and fully analyzed after completion

Drug-induced hyperuricemia and gout present an increasingly prevalent problem in clinical practice. Herein, we review the urate-lowering or urate-raising effects of commonly used agents. We performed a PubMed search using the terms gout, urate, and medication, along with the specific agents/classes described herein. Reports were reviewed until 2022, and original studies were considered if they primarily or secondarily reported the effects of 1 or more drugs on serum urate level. Previous reviews were assessed for references to additional studies that described urate-altering effects of medications. Urate-changing drugs are summarized regarding their magnitude of effect, mechanism of action, and clinical significance. Potentially urate-lowering drugs include angiotensin II receptor blockers, calcium channel blockers, high-dose aspirin and salicylates, some nonsalicylate nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, sodium-glucose cotransporter 2 inhibitors, statins, and fenofibrate. Potentially urate-increasing drugs discussed include diuretics, β-blockers, insulin, pyrazinamide, ethambutol, calcineurin inhibitors, low-dose aspirin, testosterone, and lactate. In patients who have or are at risk for hyperuricemia or gout, an increased awareness of drugs that affect serum urate level may allow for prescribing that effectively treats the indicated problem while minimizing adverse effects on hyperuricemia and gout.

BACKGROUND:Gout is the most common cause of inflammatory arthritis in adults. Gout predominantly affects the peripheral joints, but an increasing number of published cases report gout affecting the spine. We used dual-energy CT (DECT) to assess the prevalence of monosodium urate (MSU) deposition in the spine of gout patients compared to controls, and to investigate whether gout or spinal MSU deposition is associated with low back pain. METHODS:25 controls and 50 gout subjects (non-tophaceous and tophaceous) were enrolled. Demographics, gout history, Aberdeen back pain score, serum urate (sU), ESR and CRP were ascertained. Subjects underwent DECT of the lumbosacral spine, which was analyzed using manufacturer's default post-processing algorithm for MSU deposition as well as a maximally-specific algorithm to exclude potential artifact. FINDINGS/RESULTS:72 subjects were analyzed (25 control, 47 gout). Gout subjects had greater BMI, serum creatinine, sU, CRP, and ESR versus controls. Using the default algorithm, MSU-coded volumes in the lumbosacral spines were significantly higher among the gout subjects vs controls (p = 0.018). 34% of gout subjects vs 4% of controls had spinal MSU-coded deposition (p = 0.0036). Applying the maximally-specific DECT post-processing algorithm, 18% of gout patients vs 0% of controls continued to demonstrate spinal MSU-coded deposition (p = 0.04). Non-tophaceous and tophaceous subjects did not differ in spinal MSU-coded deposition or sU. Gout patients had more back pain than controls. INTERPRETATION/CONCLUSIONS:A significant subpopulation of gout patients have spinal MSU-coded lesions. Default and maximally-specific MSU post-processing algorithms yielded different absolute MSU-coded volumes, but similar patterns of results. Gout patients had more back pain than controls. Spinal MSU deposition in gout patients may have implications for clinical picture and treatment.

Caffeine is a regular part of the diet of many adults (coffee, tea, soft drinks, and energy drinks). Multiple molecular effects of caffeine suggest that it may promote bone loss. Given the extensive consumption of caffeine worldwide, any impact of caffeine consumption on bone strength and/or density would have large population health implications. The most well-established pharmacological effect of caffeine is non-specific antagonism of adenosine receptors. Adenosine regulates bone metabolism in a complex manner, with in vitro studies suggesting that direct stimulation of adenosine A_2A and A_2B receptors induces bone formation by activating osteoblasts and suppressing osteoclast differentiation and function. Thus, competitive inhibition of adenosine A₂ receptors by caffeine may inhibit bone formation and promote bone resorption. However, antagonism of adenosine A₁ receptors may have opposing effects. Caffeine has also been suggested to affect bone through derangement of calcium metabolism, alteration of vitamin D responses, and other mechanisms. In clinical and population-based studies, the impact of caffeine consumption on bone metabolism offers a mixed picture, with some but not all studies suggesting a potential link between caffeine intake and reduced bone mineral density or increased fracture risk. Differences in methodology, selected populations, and duration/timing of the studies may account for study outcome discrepancies. The in vitro effects of caffeine on cells involved in bone metabolism suggest that caffeine intake may promote osteoporosis, and some but not all clinical studies support a modest adverse caffeine impact. Herein, we describe the basic biology of caffeine as it pertains to bone, review the clinical literature to date, and consider the implications of the current data on clinical practice and future studies.

As the nation seeks to recruit and retain physician-scientists, gaps remain in understanding and addressing mitigatable challenges to the success of faculty from underrepresented minority (URM) backgrounds. The Doris Duke Charitable Foundation Fund to Retain Clinical Scientists program, implemented in 2015 at 10 academic medical centers in the United States, seeks to retain physician-scientists at risk of leaving science because of periods of extraordinary family caregiving needs, hardships that URM faculty-especially those who identify as female-are more likely to experience. At the annual Fund to Retain Clinical Scientists program directors conference in 2018, program directors-21% of whom identify as URM individuals and 13% as male-addressed issues that affect URM physician-scientists in particular. Key issues that threaten the retention of URM physician-scientists were identified through focused literature reviews; institutional environmental scans; and structured small- and large-group discussions with program directors, staff, and participants. These issues include bias and discrimination, personal wealth differential, the minority tax (i.e., service burdens placed on URM faculty who represent URM perspectives on committees and at conferences), lack of mentorship training, intersectionality and isolation, concerns about confirming stereotypes, and institutional-level factors. The authors present recommendations for how to create an environment in which URM physician-scientists can expect equitable opportunities to thrive, as institutions demonstrate proactive allyship and remove structural barriers to success. Recommendations include providing universal training to reduce interpersonal bias and discrimination, addressing the consequences of the personal wealth gap through financial counseling and benefits, measuring the service faculty members provide to the institution as advocates for URM faculty issues and compensating them appropriately, supporting URM faculty who wish to engage in national leadership programs, and sustaining institutional policies that address structural and interpersonal barriers to inclusive excellence.

Randomized controlled trials (RCTs) remain the gold standard to evaluate clinical interventions, producing the highest level of evidence while minimizing potential bias. Inadequate recruitment is a commonly encountered problem that undermines the completion and generalizability of RCTs-and is even more challenging when enrolling amidst a pandemic. Here, we reflect on our experiences with virtual recruitment of non-hospitalized patients in the United States for ColCorona, an international, multicenter, randomized, placebo-controlled coronavirus disease 2019 (COVID-19) drug trial. Recruitment challenges during a pandemic include constraints created by shelter-in-place policies and targeting enrollment according to national and local fluctuations in infection rate. Presenting a study to potential participants who are sick with COVID-19 and may be frightened, overwhelmed, or mistrusting of clinical research remains a challenge. Strategies previously reported to improve recruitment include transparency, patient and site education, financial incentives, and person-to-person outreach. Active measures taken during ColCorona to optimize United States recruitment involved rapid expansion of sites, adjustment of recruitment scripts, assessing telephone calls versus text messages for initial contact with participants, institutional review board-approved financial compensation, creating an infrastructure to systematically identify potentially eligible patients, partnering with testing sites, appealing to both self-interest and altruism, and large-scale media efforts with varying degrees of success.

BACKGROUND:The relative efficacy and safety of allopurinol and febuxostat when used according to current guidelines for the treatment of hyperuricemia are unknown. This double-blind noninferiority trial examined these issues. METHODS:Participants with gout and hyperuricemia (with at least 33% having stage 3 chronic kidney disease) were randomly assigned to allopurinol or febuxostat in this 72-week trial, with doses titrated to target serum urate. The trial had three phases: titration (weeks 0 to 24), maintenance (weeks 25 to 48), and observation (weeks 49 to 72). Allopurinol and febuxostat were initiated at daily doses of 100 and 40 mg, with maximum titration to 800 and 120 mg, respectively. Antiinflammatory prophylaxis was given during phases 1 and 2. The primary end point was the proportion of patients experiencing one or more flares during phase 3, with a prespecified noninferiority margin of less than 8 percentage points between allopurinol and febuxostat. Secondary end points included efficacy in patients with chronic kidney disease, proportion achieving target serum urate levels, and serious adverse events. RESULTS:This study included 940 participants; 20.1% withdrew, with similar proportions in treatment arms. During phase 3, 36.5% of allopurinol-treated participants had one flare or more compared with 43.5% of febuxostat-treated participants (P<0.001 for noninferiority). Overall, 80% of participants achieved mean target urates during phase 2 with no differences by treatment. There were no treatment differences (including cardiovascular events) in serious adverse events. CONCLUSIONS:Allopurinol and febuxostat achieved serum urate goals in patients with gout; allopurinol was noninferior to febuxostat in controlling flares. Similar outcomes were noted in participants with stage 3 chronic kidney disease. (Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; ClinicalTrials.gov identifier, NCT02579096.).