Faculty Bibliography

Cytokine panels measure plasma levels of a set of soluble cell-effector biomarkers and are designed to provide a snapshot of the inflammatory milieu present in a patient at the time of sampling. During the uncertainty of the COVID-19 pandemic, patients demonstrated an inflammatory response with unequivocal marked cytokine storm. Thus, physicians and investigators ordered a superfluity of cytokine panels to gain mechanistic understanding of the pathology driven by the deadly viral infection. Although cases of COVID-19 have since waned, physicians continue to send cytokine panels with evolving evidence-based indications to evaluate other inflammatory syndromes. Cytokine panels hold diagnostic utility and promise, but more research is needed to determine the extent to which these panels can be used and the clinical contexts in which they can improve diagnostic and management capabilities.

OBJECTIVE:Knee osteoarthritis (KOA) causes pain and progressive disability, but pharmacologic treatments are limited. Colchicine inhibits inflammation that might modulate KOA, but efficacy trials have yielded mixed results. We tested whether colchicine, without concurrent NSAIDs, improved KOA pain, function, synovial effusion size, and OA-associated inflammatory serum biomarkers. METHODS:Participants with symptomatic KOA and radiographic Kellgren-Lawrence grades 2/3 were randomized to receive three months of daily colchicine or placebo in a double-blind manner, with no concurrent NSAID use. The primary outcome was between-group change in visual analog score (VAS) for index knee pain. Secondary outcomes included changes in Knee Osteoarthritis Outcome Scores (KOOS), size (depth in millimeters) of sonographically-identified effusions, acetaminophen use, and changes in OA-related serum biomarkers. RESULTS:, IL-1ra, IL-8, and VEGF (p < 0.16). CONCLUSION/CONCLUSIONS:This double-blind placebo-controlled trial of colchicine for KOA failed to demonstrate improvement in pain, function, or synovial effusion size in comparison to placebo at three months. Early improvement in OA-associated inflammatory biomarkers suggests a possible longer-term clinical benefit. Clinical Trials Registration No NCT03913442.

Prior research suggests a connection between osteoarthritis and gout at sites commonly affected by gouty attacks. Whether this connection exists at sites with known monosodium urate crystal deposition but less commonly affected by gouty attacks, such as the lumbosacral spine, has not been previously investigated. We assessed whether lumbosacral osteoarthritis is more prevalent and more severe in subjects with gout compared with controls, and whether lumbosacral osteoarthritis is associated with higher levels of spinal monosodium urate deposition. Fifty gout subjects and 25 controls underwent dual-energy computed tomography imaging of the lumbosacral spine. We assessed lumbosacral osteoarthritis using a modification of a validated computed tomography scoring system, incorporating grade of intervertebral disc narrowing and facet joint osteoarthritis, and presence of spondylolysis and spondylolisthesis. We quantified spinal monosodium urate deposition using the default post-processing algorithm, plus a maximally specific algorithm to exclude potential artefacts. Forty-six gout subjects and 25 controls, average age 62 years, were included in the final analysis. Both gout and control subjects exhibited high rates of facet joint osteoarthritis and degenerative disc disease, with no difference in prevalence or severity between groups. Gout subjects did not have differing prevalence of spondylolysis and spondylolisthesis vs. controls. Subjects with lumbosacral osteoarthritis did not have higher levels of spinal monosodium urate deposition. Overall, lumbosacral osteoarthritis was not more prevalent or more severe in gout patients compared with controls, and spinal monosodium urate crystal deposition did not differ between patients with and without lumbosacral osteoarthritis.

OBJECTIVE:DISSOLVE I and II examined efficacy and safety of nanoencapsulated sirolimus (NAS) plus pegadricase (NASP) in patients with uncontrolled gout (UG). METHODS:In these double-blind, placebo-controlled Phase 3 trials of NASP, patients were randomized 1:1:1 to infusions of high-dose (HD) or low-dose (LD) NAS plus pegadricase (HD NASP, LD NASP, respectively) or placebo, given every 4 weeks for 6 doses. The primary endpoint was proportion of patients with serum urate (SU) <6 mg/dL for ≥80% of the time during Weeks 21-24. Secondary endpoints included health-related quality of life, tophus resolution, tender joints, and gout flares. Safety was also assessed. RESULTS:Overall, 265 patients received HD NASP, LD NASP, or placebo. SU response during Weeks 21-24 was significantly higher with NASP than placebo (HD NASP: 51%; LD NASP: 43%; placebo: 8%; p<0.0001 for both doses vs placebo). Common adverse events included gout flares (HD NASP: 42.5%; LD NASP: 44.3%; placebo: 43.3%), infections (HD NASP: 23.0%; LD NASP: 18.2%; placebo: 16.7%), and stomatitis (HD NASP: 9.2%; LD NASP: 3.4%; placebo: 0%). Infusion reactions within 1 hour were infrequent (4%) in NASP-treated patients. During Weeks 1-12, the proportion of patients with flares was similar between NASP- and placebo-treated patients; thereafter, it decreased in NASP-treated patients but remained unchanged with placebo. CONCLUSION/CONCLUSIONS:NASP treatment resulted in a significantly higher proportion of patients with complete SU response during Weeks 21-24 compared to placebo and was generally well-tolerated. NASP, an every-4-week treatment, can markedly alleviate disease burden in patients with UG.

BACKGROUND:While treat-to-target urate-lowering therapy (ULT) is endorsed as best practice in gout management, limited data exist on its impact on health-related quality of life (HRQoL). We assessed the impact of treat-to-target ULT on HRQoL among participants receiving protocolized gout care, identifying factors associated with HRQoL and HRQoL change. METHODS:This was a post-hoc analysis of a 72-week randomized trial, pooling data from allopurinol and febuxostat treatment arms. The VR-12 and EQ-5D-3L were administered at baseline, 24-, 48-, and 72-weeks. HRQoL changes over follow-up were examined using paired t-tests. Factors associated with baseline HRQoL were evaluated using multivariable linear regression. General estimating equations (GEE) were used to identify determinants of HRQoL change over follow-up. RESULTS:Participants (n=878) in this analysis were 98.9% male, had a mean age of 62.4 years, and 67.4% self-reported White race. HRQoL scores overall, and particularly the domains of physical function, mobility and pain, improved significantly over 72-weeks (p<0.001) with improvements noted by 24-weeks. Poorer enrollment HRQoL was associated with younger age, non-White race, tophi (for EQ-5D-3L), higher serum urate, and greater comorbidity. Baseline factors associated with HRQoL improvements over 72-weeks of ULT included lower C-reactive protein and lower comorbidity scores with similar changes observed by ULT assignment. CONCLUSIONS:Treat-to-target ULT in gout is accompanied by HRQoL improvements evident by 24-weeks and sustained through 72-weeks. HRQoL gains with treat-to-target ULT are most prominent in the domains of physical function, mobility, and pain and are greatest in those with lower baseline levels of inflammation and comorbidity.

Gout is the most common inflammatory arthritis. Treatment of gout includes anti-inflammatory and urate-lowering agents. Robust guidelines by the American College of Rheumatology, the European Alliance of Associations for Rheumatology and other committees have been released regarding recommendations for urate-lowering therapy, including suggested first- and second-line medications, length of therapy with prophylaxis, and target serum urate concentration to treat patients to. Notably, the American College of Physicians guidelines do not recommend robust urate lowering and are more geared towards treating symptoms without monitoring or lowering urate. Controversies regarding the optimal management of gout patients still exist. In the following, we discuss several of these controversies and some of the most recent literature regarding potential future changes in recommended management of gout. We discuss options for prophylactic therapy and length, treating gout concomitantly with its most common comorbidities, hypertension, diabetes mellitus, and cardiovascular disease, potential debulking therapy for more severe gout, and optimal urate levels.

OBJECTIVES/OBJECTIVE:We tested the hypotheses that individuals with gout would have distinct circulating inflammatory biomarker patterns compared with non-gout controls and that these differences would be attenuated with highly-effective urate-lowering therapy (ULT). METHODS:This case-control and longitudinal cohort study utilized longitudinal serum samples from a subset of participants from the STOP Gout study and non-gout controls from an institutional biobank at a single time point. Twenty pre-selected inflammatory and cardiometabolic biomarkers were measured and varimax-rotated principal component analysis (PCA) performed. An inflammatory score was generated using standardized biomarker values representing PCs associated with gout and compared between controls and gout patients, and among gout patients over time. A generalized estimating equation was used to assess interactions between clinical factors and change in inflammatory score over time. RESULTS:Five PCs statistically differed in gout (n = 278) at baseline vs. controls (n = 275) after accounting for covariates. Mean inflammatory scores of gout cases at all three time points were increased vs. controls (p < 0.001). There was a decrease in inflammatory scores at both 24- (p = 0.01) and 48-weeks (p < 0.001) vs. baseline among gout cases. Higher baseline score and time were associated with reductions in inflammatory score, whereas hypertension and higher baseline serum urate were associated with an increased inflammatory score. CONCLUSION/CONCLUSIONS:Gout is characterized by distinct patterns of circulating inflammatory biomarkers and these appear to change over time with treat-to-target ULT to approximate controls. This study supports the importance of treat-to-target ULT in gout management not only for flare prevention, but also to mitigate systemic inflammation.

OBJECTIVE:Though gout guidelines endorse treat-to-target urate-lowering therapy (ULT), its long-term durability following treat-to-target implementation has not been extensively studied. Examining follow-up data from a trial implementing treat-to-target management, we evaluated the frequency and determinants of ULT persistence. METHODS:This analysis examined participants completing the 72-week STOP Gout trial with available follow-up data extending 2-years post-study. Participants were followed passively using administrative and electronic health record data with persistence defined by a ULT dispensing episode overlapping with the 2-year post-study time point. Associations of participant factors with ULT persistence were examined using multivariable logistic regression. RESULTS:Participants in this analysis (n = 638) were predominantly male (99 %) and had a mean age of 62.7 years. At 2-years post-study, 66 % continued ULT. Adjusting for covariates, ≥2 rheumatology visits post-study (vs. none) was associated with greater ULT persistence (aOR 1.75; 95 % CI 1.13-2.72). ULT persistence was lower in individuals reporting Black/African American race (aOR 0.56; 95 % CI 0.36-0.87), Hispanic ethnicity (aOR 0.21; 95 % CI 0.09-0.50), and better quality-of-life at the beginning of post-study follow-up. Though not reaching significance, achievement of serum urate goal at 48-weeks during STOP Gout study demonstrated a borderline association with greater long-term persistence (aOR 1.68; 95 % CI 0.99-2.85). CONCLUSION/CONCLUSIONS:Though interventions implementing treat-to-target ULT have demonstrated efficacy in trials, this study suggests that such interventions may have limited durability following transitions back to real-world gout management. The issue of limited treatment durability appears to be compounded among underrepresented patient populations and improved in the context of ongoing rheumatological care.