Faculty Bibliography

OBJECTIVE:Using trial data comparing treat-to-target allopurinol and febuxostat in gout, we examined participant characteristics associated with serum urate (SU) goal achievement. METHODS:Participants with gout and SU ≥6.8 mg/dL were randomized to allopurinol or febuxostat, titrated during weeks 0 to 24, and maintained weeks 25 to 48. Participants were considered to achieve SU goal if the mean SU from weeks 36, 42, and 48 was <6.0 mg/dL or <5 mg/dL if tophi were present. Possible determinants of treatment response were preselected and included sociodemographics, comorbidities, diuretic use, health-related quality of life (HRQoL), body mass index, and gout measures. Determinants of SU response were assessed using multivariable logistic regression with additional analyses to account for treatment adherence. RESULTS:Of 764 study participants completing week 48, 618 (81%) achieved SU goal. After multivariable adjustment, factors associated with a greater likelihood of SU goal achievement included older age (adjusted odds ratio [aOR] 1.40 per 10 years), higher education (aOR 2.02), and better HRQoL (aOR 1.17 per 0.1 unit). Factors associated with a lower odds of SU goal achievement included non-White race (aORs 0.32-0.47), higher baseline SU (aOR 0.83 per 1 mg/dL), presence of tophi (aOR 0.29), and the use of diuretics (aOR 0.52). Comorbidities including chronic kidney disease, hypertension, diabetes, and cardiovascular disease were not associated with SU goal achievement. Results were not meaningfully changed in analyses accounting for adherence. CONCLUSIONS:Several patient-level factors were predictive of SU goal achievement among patients with gout who received treat-to-target urate-lowering therapy (ULT). Approaches that accurately predict individual responses to treat-to-target ULT hold promise in facilitating personalized management and improving outcomes in patients with gout.

OBJECTIVE:Transparency of disclosure in publication is necessary for readers to be aware of any potential conflicts of interest (PCOIs). Past studies of accuracy of disclosure in rheumatology journals have focused exclusively on clinical practice guidelines and not research works. We assessed discrepancy in reporting PCOIs in clinically oriented manuscripts published in the three top-ranked (by impact factor) US-based general rheumatology journals. METHODS:We reviewed disclosures provided by first, second, and last authors of 50 published clinically oriented articles in each of the three top-ranked general US rheumatology journals. For each author, we extracted payment reports from the Open Payments Database (OPD) related to consulting fees, honoraria, and speaker or faculty compensation. We defined a PCOI as a payment received from a company with an ongoing clinical trial or a medication on the market related to the manuscript's subject matter within the 36 months before the online publication date. We additionally analyzed each author individually to determine whether their reported disclosures matched PCOIs from the OPD. RESULTS:Of 150 articles analyzed, 101 included authors with PCOIs. Ninety-two of these 101 publications (92%) contained inaccurate (non- or under-) disclosures. Among 135 authors with PCOIs, 118 reported inaccurately (87%). All 14 articles that published clinical trial results (and all 23 of their qualifying authors) had disclosure inaccuracies. CONCLUSION/CONCLUSIONS:Inaccurate financial disclosure by authors remains an issue in clinically oriented research studies reported in top rheumatology journals. Improved community education and firmer expectations would permit readers to better assess any possible impact of PCOIs on publications.

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.

Accessing a joint with a needle (arthrocentesis) to extract synovial fluid is a skill intrinsic to the rheumatologist's praxis. Joint aspirations are essential for diagnosing or excluding septic joints, are the gold standard for diagnosing acute crystal arthritis, and can provide valuable information about the nature of other forms of arthritis. In appropriate settings, injecting medications into joints can provide rapid, temporary, or even prolonged relief of pain and swelling and can provide a window of relief until other treatment modalities (anti-inflammatories, immunomodulators, and physical therapy) can enforce durable responses. Soft tissue aspirations (e.g., of bursae) and soft tissue injections (of bursae, tendons, trigger points, and areas of nerve compression) can provide similar relief, earning the practitioner the gratitude of the patient. Here, we provide a primary on joint and soft tissue aspiration and injection, including indications for and against procedures, preparing for procedures, and approaches to specific musculoskeletal structures.

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.