Objective Through binding to folate receptor-β (FR-β), the new 99mTc–EC20 (Etarfolatide) imaging technique detects activated but not resting macrophages in vivo. The goal of this study was to investigate macrophage-related inflammation in osteoarthritis (OA). Methods Twenty-five individuals (50 knees) with symptomatic OA of at least one knee underwent SPECT-CT imaging of both knees and planar imaging of the whole body after injection of Etarfolatide. Scans and knee radiographs were scored blinded to clinical information including knee and other joint site pain severity. Measures of association controlled for age, gender, BMI and employed repeated measures to adjust for correlation between knees. Design Activated macrophages were present in the majority (76%) of knees. The quantity of knee-related macrophages was significantly associated with knee pain severity (R=0.60, p<0.0001) and radiographic knee OA severity including joint space narrowing (R=0.68, p=0.007), and osteophyte (R=0.66, p=0.001). Macrophages were also localized to joints commonly affected by OA including hand finger joints (12%), thumb bases (28%), shoulders (26%), great toes (18%) and ankles (12%). The presence of joint pain at fingers, wrists, ankles and great toes was significantly positively associated with presence of activated macrophages at these sites (p<0.0001–0.04). Conclusions This study provides the first direct in vivo evidence for macrophage involvement in OA in a substantial proportion of human knees. The association of quantity of activated macrophages with radiographic knee OA severity and joint symptoms suggests that drugs targeting macrophages and macrophage-associated inflammatory pathways may have the potential to be both symptom and structure modifying.

To assess the safety, tolerability, and pharmacology of LY3023703, a microsomal prostaglandin E synthase 1 (mPGES1) inhibitor, a multiple ascending dose study was conducted. Forty-eight subjects received LY3023703, celecoxib (400 mg), or placebo once daily for 28 days. Compared with placebo, LY3023703 inhibited ex vivo lipopolysaccharide-stimulated prostaglandin E2 (PGE2 ) synthesis 91% and 97% on days 1 and 28, respectively, after 30-mg dosing, comparable to celecoxib's effect (82% inhibition compared to placebo). Unlike celecoxib, which also inhibited prostacyclin synthesis by 44%, LY3023703 demonstrated a maximal increase in prostacyclin synthesis of 115%. Transient elevations of serum aminotransferase were observed in one subject after 30-mg LY3023703 dosing (10× upper limit of normal (ULN)), and one subject after 15-mg dosing (about 1.5× ULN). Results from this study suggest that mPGES1 inhibits inducible PGE synthesis without suppressing prostacyclin generation and presents a novel target for inflammatory pain.

NCT02192190.

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BackgroundThe safety and efficacy of galcanezumab, a monoclonal antibody directed against CGRP, were assessed in a phase 2 clinical trial NCT02192190 in patients with moderate to severe osteoarthritis (OA) knee pain. Patients were randomized to placebo, galcanezumab (5, 25, 120 and 300 mg subcutaneously every 4 weeks, at weeks 0 and 4) or celecoxib (200 mg once daily) for 16 weeks in a 2:1:1:1:1:1 ratio. The study was terminated after an interim analysis due to inadequate efficacy for OA pain.ObjectivesThis study assessed the correlation of baseline plasma CGRP concentrations with signs, symptoms and radiographic severity of OA, and response to galcanezumab and celecoxib treatments.MethodsPlasma samples were collected at baseline and weeks 4, 8, 12 and 16 after study drug treatment. CGRP concentrations were determined by a validated high sensitivity (HS) assay. Correlation of baseline CGRP levels to WOMAC scores, PGA and radiographic Kellgren-Lawrence (K-L) grades were assessed using Spearman's correlation and Wilcoxon test. Patients were stratified into high vs low groups by baseline CGRP concentrations and post-treatment changes from baseline WOMAC scores evaluated by mixed effect model repeated measures for each subset.ResultsAt the interim analysis, baseline plasma CGRP samples were available for 262 patients with 54 patients providing samples at study termination through the week 8 visit. The median CGRP concentration at baseline was 1.07 pg/ml, range <0.78 to 33.91, and 31% of patients were below the level of quantitation (BLQ, <0.78 pg/ml). Median baseline CGRP levels were 1.0 pg/ml for K-L grade 2 (N=178), and 1.2 pg/ml for K-L grade 3 (N=84) (p=0.06). Correlations of WOMAC or PGA scores with baseline CGRP levels were all r <0.01 (showed no significant correlations). In OA patients receiving galcanezumab 300mg SC at week 0 and week 4, those with high baseline CGRP levels demonstrated a 14mm improvement in WOMAC Pain response at week 12, (95% CI 0, 29mm). The pain response to galcanezumab 300mg did not reach the magnitude of celecoxib response and no effects were seen at 5–120mg doses. Celecoxib treatment had larger pain reduction among patients with high baseline CGRP compared to low baseline CGRP levels. Treatment with celecoxib did not alter plasma CGRP concentrations.ConclusionsAt baseline, CGRP levels in OA patients were not associated with WOMAC or PGA scores. There was a modest association to radiographic K-L grade. Subgroup analyses of patients with high (>median) CGRP levels at baseline suggested a potential response to galcanezumab for the highest dose, 300mg, but not lower doses. Celecoxib response was greater in those with higher CGRP levels. However, interpretation was limited by small samples sizes at the latter time points. Further studies may determine if enriching the OA population for higher CGRP levels at baseline, or if increased or longer dosing of galcanezumab would improve pain responses or if CGRP blockade is relevant in relieving OA knee pain.Disclosure of InterestT. Mcnearney Share...

8pm). To characterize the statistical properties of the time series of pain ratings, the means of the pain ratings in three blocks were calculated and compared by one way analysis of covariance. As well, fractal dimension, D, was calculated using rescaled range analysis to characterize the OA participants' pain fluctuations. Results: Thirty-two individuals participated in the study (18 females, age (mean, standard deviation) 59.7 AE6.5 yr; 10 males, 55.3AE6.7 yr). As shown in Figure A, there is no significant difference among the three blocks of time for the mean rating of pain. Figure B displays the distribution of fractal dimension, D. calculated for each individual's mean daily pain intensity. The mean fractal dimension, D, for the population is 1.65AE0.04, which signifies an anti-persistent pain time series. Conclusions: This is the first analysis to characterize the fractal dimension of OA pain. The finding of anti-persistent time series means that on average more intense pain is followed by lesser pain, a finding very similar to that reported for chronic low back pain and in contrast to both purely neuropathic pain and acute pain. Whereas these previous studies were over short time periods, this study suggests that power law scaling can be preserved for much longer periods of time (weeks or months), which is significant for clinical application. The anti-persistent pattern of pain is consistent with the concept of central pain processes activated to modulate peripheral pain input in OA.

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