Faculty Bibliography

Antibiotic therapy against non-tuberculous mycobacteria (NTM) is prolonged and can be associated with toxicity. We sought to evaluate whether chest physical therapy (PT) was associated with clinical improvement in patients with NTM not receiving anti-mycobacterial pharmacotherapy. A retrospective review of 77 subjects that were followed from June 2006 to September 2014 was performed. Baseline time point was defined as the first positive sputum culture for NTM; symptoms, pulmonary function, and radiology reports were studied. Subjects were followed for up to 24 months and results analyzed at specified time points. Half of the subjects received chest PT at baseline. Cough improved at 12 (p = 0.001) and 24 months (p = 0.003) in the overall cohort when compared with baseline, despite lack of NTM antibiotic treatment. Cough decreased at 6 (p = 0.01), 9 (p = 0.02), 12 (p = 0.02) and 24 months (p = 0.002) in subjects that received chest PT. Sputum production also improved at 24 months in the overall cohort (p = 0.01). There was an increase in the percent change of total lung capacity in subjects that received chest PT (p = 0.005). Select patients with NTM may have clinical improvement with chest PT, without being subjected to prolonged antibiotic therapy. Future studies are warranted to prospectively evaluate outcomes in the setting of non-pharmacologic treatment and aid with the decision of antibiotic initiation.

Background/Purpose: In 2008, 18% of rheumatology fellowship program (RFP) program directors (PDs) included musculoskeletal ultrasound (MSUS) in their training programs. Overall goal of this study was to assess the current state and ascertain the needs for MSUS education among RFPs. The objective of this study was to determine if fellowship program size impacts inclusion of MSUS in training. Methods: Out of two surveys sent via QualtricsTM in 2015, a 13-item needs assessment survey was sent to all RFP PDs determining implementation of MSUS teaching including machine accessibility, faculty training, and institutional support. The second survey assessed teaching and evaluation methods used. For the first survey, Fischer's Exact Test was used to test differences between fellowship programs based on size. Small programs were defined as programs with 1-2 fellows yearly, while big programs were those with at least 3 fellows yearly. Results: Out of 113 RFPs, 103 (91%) PDs responded to the needs assessment survey. In total, 94% of RFPs are currently offering some form of MSUS training. Of 73 small programs, 91.8% offered MSUS training; 97.1% of big programs offered MSUS training. By large, there was no statistically significant difference between small and big programs (p=0.429). Majority of both small and big programs (81.8 vs. 93.9%) cited at least one faculty who was competent in performing MSUS (p=0.212). Majority of the teaching was done by a key clinical faculty member other than the PD (39.7% vs. 54.5%). Majority owned an US machine (72.1 vs. 87.9%; p=0.037). When asked if they wanted MSUS to be part of the Rheumatology fellowship training curriculum, majority wanted its inclusion however most wanted it they wanted MSUS to be part of the Rheumatology fellowship training curriculum, majority wanted its inclusion however most wanted it only to be optional (66.2% vs. 66.7%), as compared to those wanted it to be a standard requirement (29.4% vs. 30.3%). Conclusion: MSUS has become prevalent among RFPs. The size of a fellowship program is not a factor in determining inclusion of a MSUS teaching program. Small programs have comparable capacity to include MSUS in teaching programs when compared to big programs. There is openness to including MSUS in Rheumatology fellowship training, whether as an optional or standard part of the curriculum

Background/Purpose: Persistent inflammation is a characteristic of several joint diseases, including OA. It is nowadays appreciated that this could be a result of a failure to (optimally) activate inflammation resolution pathways. Therefore, we investigated the presence of specialized pro-resolving lipid mediators (SPM) and their precursors as pathway markers of the resolution process in the joint of OA patients and controls. Methods: SF was obtained from knee OA (2 populations) and rheumatoid arthritis (RA) patients fulfilling the ACR criteria for OA and RA, respectively, and healthy controls. Lipid mediators (LMs) were determined by targeted lipidomics using liquid-chromatography mass spectrometry. Sixty different lipids including pro-inflammatory (e.g. prostaglandins, leukotrienes) and anti-inflammatory/pro-resolving LM (e.g. SPM), as well as their precursors can be detected with our technique. Results: SF from 24 OA and 12 RA patients were first studied. Thirty-seven lipids were detected in the soluble fraction of SF, including polyunsaturated fatty acids (PUFA) and their lipoxygenase (LOX) and cyclooxygenase (COX) pathway markers in both OA and RA patients. Among these, pro-inflammatory LM such as PGE2 and thromboxane B2, as well as the pathway markers of resolution and precursors of SPM, 17-HDHA and 18-HEPE, were detected. Except for the LOX products of arachidonic acid: 15-HETE, 6-trans-LTB4 and 20-OH- LTB4, which were lower in OA than in RA SF, all other lipid mediators and PUFA were comparable between OA and RA samples. Ratios of metabolites to their precursors indicated that both pro- (e.g. LTB4) and anti-inflammatory LOX products (e.g. 17- HDHA) are more efficiently generated in RA than in OA patients, while no differences were observed in COX products. Interestingly, the SPM resolvin D2 (RvD2) could also be detected, but only in the insoluble fraction (cells and undigested matrix), indicating that the resolution pathways are activated in OA. This expands our previous publication showing activation of resolution in RA patients. To assess the efficiency of activation of resolution in OA, we have performed targeted lipidomics on total SF in an additional study with 32 OA patients and 10 healthy controls. Confirming earlier data, most LMs were also detected in this study, including the pro-inflammatory PGE2, the SPM precursors 17-HDHA and 18-HEPE, and the SPM RvD2. Additionally, we detected 18S-resolvin E3 (18S-RvE3). Remarkably, both the absolute concentrations of the SPM RvD2 and 18S-RvE3, and the ratio to their precursors, 17-HDHA and 18-HEPE, were lower in OA compared to healthy SF, indicating less efficient generation of SPM in OA compared to healthy joints. In contrast, the proinflammatory lipid PGE2was higher in OA than in healthy SF, indicating that the lower activation of resolution is paired by a higher inflammatory load in OA compared with healthy individuals. Conclusion: By using a state-of-the-art technique, we show for the first time that resolution pathways are activated in OA patients. Importantly, resolution seems to be less efficiently activated than in healthy individuals, which could account for the persistent inflammation observed in OA and RA patients

Background/Purpose: Growing numbers of studies show increased expression in Osteoarthritis (OA) of inflammatory cytokines, such as IL-1beta and TNFalpha, in joint tissues and peripheral blood mononuclear (PBM) cells. The IL1 receptor antagonist (IL1RN) gene cluster region has been associated with susceptibility to knee OA, thereby further implicating inflammation in OA pathogenesis. In these studies, we examined the association of IL-1RN haplotype with the radiographic severity of symptomatic knee OA (SKOA). Methods: Genomic DNA from SKOA patients from three cohorts (NYU I, NYU-II and O

Background/Purpose: Gout is an independent risk factor for cardiovascular disease (CVD). Investigators studying the relationship between gout and CVD have focused on acute coronary outcomes, with limited evidence available regarding peripheral arterial function. Using high-resolution ultrasound imaging of the brachial artery, we examined endothelial and smooth muscle arterial function in gout subjects versus healthy controls. Methods: 34 untreated male gout subjects and 64 healthy control males were included. By enrollment criteria some gout subjects, but no healthy controls, had coronary artery disease (CAD) or diabetes, or were current smokers. Demographics and medical history were recorded. Participants underwent brachial artery flow-mediated dilation (FMD; arterial response to blood flow after transient interruption using a distal blood pressure cuff) and nitroglycerine-mediated dilation (NMD) to assess endothelium-dependent and independent arterial smooth muscle responsiveness, respectively. Dynamic ultrasound images were assessed by two independent observers, with results reported as percentage change in arterial diameter from baseline. Results: Compared with healthy controls, gout subjects had a higher prevalence of CAD (21% vs 0%, p<0.05), chronic kidney disease (76% vs 0, p<0.05), hypertension (71% vs 22%, p<0.05) and hyperlipidemia (50% vs 18%, p<0.05), but a similar low prevalence of diabetes (6% vs 0%, p=0.12). 29% of gout patients were current smokers (p vs control<0.05). Gout subjects were slightly older (58.9 vs 53.2 years, p<0.05), and significantly more gout patients were African American (44% vs 8%). Both FMD (2.20+/-3.12 vs 3.56+/-2.50, p=0.021) and NMD (16.69+/-9.01 vs 24.51+/-7.18, p=0.00002) were significantly reduced in the gout group vs controls. Gout nonsmokers, white gout patients, and gout patients lacking specific co-morbidities persisted in having decreased FMD and NMD compared with controls. Gout patients with versus without specific co-morbidities had similar degrees of impaired FMD and NMD. Analysis of the gout group showed an inverse Pearson correlation between FMD and CRP (R=-0.42, p=0.017), a trend for inverse Pearson correlation between FMD and serum urate (R=-0.31, p= 0.08); but no correlation between NMD and CRP or serum urate. Conclusion: Compared with healthy controls, patients with gout have reduced arterial function as measured by FMD and NMD. While the increased prevalence of comorbidities among gout patients may contribute to diminished arterial function, it appears to be insufficient to explain the endothelial and smooth muscle dysfunction observed. Hyperuricemia and chronic inflammation may contribute to endothelial dysfunction among gout patients, but do not appear to contribute to smooth muscle dysfunction. Whether appropriate gout therapy may improve FMD and NMD in gout patients remains to be determined. (Figure Presented)

Background/Purpose: Osteoarthritis (OA) etiopathogenesis includes an inflammatory component. Published reports indicate that synovial fluid urate levels, even in patients without gout, associate with OA prevalence/severity. Whether serum urate (sUA), the precursor for gout and a biomarker for cardiovascular and kidney disease, may serve as a biomarker to convey or predict OA risk is not known. We investigated whether sUA levels associate with knee OA radiographic severity and contrast MRI-measured quantitative synovial volume (SV), and whether sUA levels predict radiographic progression, in a gout-free knee OA cohort. Methods: We assessed sUA in 88 gout-free subjects who completed a 24-month prospective, natural history knee OA study. Subjects had symptomatic medial knee OA, met ACR knee OA criteria and had BMI <33 at study entry. sUA was measured (enzyme-colorimetry) in serum frozen and banked at baseline. At baseline and 24 months, patients underwent standardized weight-bearing fixed-flexion posteroanterior knee radiographs (SynaFlexerTM). Twenty-seven subjects additionally had a dynamic gadolinium-enhanced 3.0T knee MRI that was read for quantitative synovial volume (SV). A musculoskeletal radiologist, blinded to subject data, determined joint space width (JSW) and Kellgren-Lawrence (KL) grades at each time point. Joint space narrowing (JSN) was determined as JSW change from baseline to 24 months. Pearson's correlations, student's t-tests, one-way ANOVA with post hoc Tukey-Kramer tests, ROC and AUC curves were used in statistical analyses, as appropriate. Results: sUA correlated with JSN in both univariate (r=0.40, p<0.01) and multivariate analyses (adjusting for age, gender and BMI, r=0.28, p=0.010). There was a significant difference in mean JSN after dichotomization of sUA at 6.8mg/dL, the solubility point for serum urate, even after adjustment for age, gender and BMI (JSN [+/-SEM] of 0.90mm+/-0.20mm for sUA>6.8; JSN [+/-SEM] of 0.31mm+/-0.09mm for sUA<6.8, p<0.01). Baseline sUA distinguished progressors (JSN>0.2mm), and fast progressors (JSN>0.5mm), from non-progressors (JSN<0.0mm) in multivariate analyses (area under the receiver operating characteristic curve [AUC] 0.626, p=0.027; AUC 0.620, p=0.045, respectively). sUA also correlated with SV (r=0.44, p=0.0040), a possible marker of JSN, though this correlation did not persist after controlling for age, gender and BMI (r=0.13, p=0.562). Conclusion: In non-gout patients with knee OA, sUA levels predict JSN and may serve as a biomarker for OA progression. (Figure presented)