Faculty Bibliography

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.).

Over the last decade, evidence has demonstrated that long-term, low-dose colchicine (0.5 mg daily) is effective for preventing gout flare and cardiovascular (CV) events in a wide range of patients. Given the potentially expanding use of colchicine in CV disease, we here review and update the biologic effects and safety of colchicine based on recent data gathered from bench and pharmacodynamic studies, clinical reports, controlled clinical trials, and meta-analyses, integrated with important studies over the last 50 years, to offer a consensus perspective by experts from multiple specialties familiar with colchicine's long-term use. We conclude that the clinical benefits of colchicine in gout and CV disease achieved at low dose do not sustain serum levels above the upper limit of safety when used in patients without advanced renal or liver disease or when used concomitantly with most medications. Further, data accrued over the last 50 years strongly suggest that the biologic effects of long-term colchicine do not increase the risk of cancer, sepsis, cytopenia, or myotoxicity.

Kikuchi-Fujimoto's disease (KFD) and adult-onset Still's disease (AOSD) are rare idiopathic inflammatory conditions of unknown etiology. Ten prior instances of KFD and AOSD occurring together have been reported in the medical literature. These overlaps, together with certain distinguishing clinical and laboratory characteristics in these co-occurrences, offer insight into the pathophysiology of both of these rare disorders. Too, examination of these cases may help improve the diagnostic evaluation and care of patients afflicted with these rare diseases. We therefore report an additional patient with KFD and AOSD occurring in a middle-aged Hispanic female patient and perform a systematic literature review using the PubMed/MEDLINE and Embase databases to further analyze and compare prior identified cases. Our observations in our index case complement and expand previous reports, including new demographic and diagnostic features not seen in prior cases of overlap. Indeed ours is the first in a patient of Hispanic ethnicity, with retroperitoneal lymphadenopathy, as well as with a skin biopsy consistent with AOSD. Each of the reviewed cases of co-occurrence met the diagnostic criteria for both KFD and AOSD. This finding, in the setting of unique clinical and diagnostic manifestations that are not typically seen in either disease entity alone, suggests the presence of an overlap syndrome. Also, many of the shared clinical features and symptomatic responses to targeted therapies implies a similar, yet still poorly understood, pathophysiologic pathway for the two diseases.

PURPOSE OF REVIEW/OBJECTIVE:Calcium pyrophosphate deposition disease (CPPD) arises from calcium pyrophosphate deposition throughout the body, leading to different clinical syndromes that may be diagnosed using various imaging modalities. The purpose of this review is to highlight recent updates in the imaging of CPPD. RECENT FINDINGS/RESULTS:Conventional radiography remains the initial test when imaging CPPD; but musculoskeletal ultrasound and conventional computed tomography (CT) may also assist in diagnosing and characterizing CPP deposits, with increased sensitivity. Dual-energy CT is also being used to differentiate CPP crystals from other crystal deposition diseases. CPP discitis has been diagnosed with MRI, but MRI has lower sensitivity and specificity than the aforementioned imaging studies in CPPD diagnosis. Assorted imaging modalities are increasingly used to diagnose CPPD involving atypical joints, avoiding invasive procedures. Each modality has its advantages and disadvantages. Future imaging may be able to provide more utility than what is currently available.

Background/Purpose: Axial gout involvement was first reported in 1950 (1). Over 100 cases have subsequently been published. Reported cases have presented as acute back pain, cord compression, and/or neurologic symptoms, with diagnosis made by invasive procedure (surgical excision or biopsy). However, the true extent of MSU deposition in the spine of gout patients, including asymptomatic patients or those with non-specific symptoms, is unknown and likely higher. We used DECT to determine the extent of MSU deposition in the lumbosacral spines of patients with gout, with and without tophi, compared to controls without gout.
Method(s): We recruited controls, nontophaceous, and tophaceous gout patients, age 45-80. Individuals with CPPD disease, RA, spondyloarthropathy, active spinal malignancy, or on urate lowering treatment (ULT) >= 6 months were excluded. Gout subjects met 2015 ACR gout classification criteria, with entry serum urate (sU) of >6.8 mg/dL ( >6.0 mg/dL if on ULT for < 6 months). Demographics, gout history, Aberdeen back pain scale, sU, ESR, and CRP were collected. Subjects underwent DECT of the lumbosacral spine (LS) to assess for MSU deposition.
Result(s): 75 subjects were enrolled, and 72 completed the study (1 nontophaceous gout patient lost to follow-up prior to DECT, 2 tophaceous excluded after sU at time of DECT found to be < 6.0mg/dL). All groups were similar in age in years (controls 61.8+/-3.8, nontophaceous 64.0+/-6.1, tophaceous 60.4+/-11.0, p=0.81) but differed in BMI (controls 28.3+/-6.5 kg/m², nontophaceous 34.1+/-7.2 kg/m², tophaceous 29.5+/-4.5 kg/m², p=0.03) and creatinine (controls 1.0+/-0.2 mg/dL, nontophaceous 1.4+/-0.7 mg/dL, tophaceous 1.4+/-0.6 mg/dL, p< 0.05). Mean sU and ESR were higher in gout subjects (sU-controls 5.3+/-1 mg/dL, nontophaceous 8.5+/-1.7 mg/dL, tophaceous 8.5+/-1.6 mg/dL, p< 0.05; ESR-controls 13.7+/-13.8 mm/h, nontophaceous 26.5+/-19.4 mm/h, tophaceous 25.1+/-15.7 mm/h, p< 0.05). Using standard DECT settings for MSU visualization, gout patients had larger MSU volumes than controls (controls 2.2+/-1.2 cm3, all gout 5.23+/-6.9 cm3; p =0.03). Tophaceous patients had numerically greater MSU deposition compared with nontophaceous (6.0+/-8.9 cm3, vs 4.4+/-4.3 cm3, ns). Reanalysis of a subset of scans using highly specific settings to eliminate artifact reduced the number of subjects with MSU signal but confirmed greater prevalence of deposition among gout patients (n=29; controls with deposition 0/9, nontophaceous with deposition 1/11, tophaceous with deposition 2/9). Back pain was also more common among gout patients. No subject had frank tophi on spinal DECT.
Conclusion(s): Gout patients have significantly greater intercritical inflammation and LS MSU deposition than controls, and trend toward greater deposition among patients with tophi. Preliminary results using the most stringent DECT threshold settings suggests MSU differences are not artifact. The complete data set is currently undergoing evaluation and the full results will be presented