Session Information
Date: Tuesday, November 10, 2015
Title: Rheumatoid Arthritis - Human Etiology and Pathogenesis Poster III
Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: Rheumatoid arthritis (RA) is associated with increased cardiovascular disease, insulin resistance, and disability. Our objectives were to analyze levels of skeletal muscle inflammatory cytokines and gene expression pathways in RA patients compared to controls without RA in order to determine whether increased muscle inflammation was related to disease activity, insulin resistance, and/or disability. We hypothesized that greater disease activity would be associated with greater muscle inflammation and worse insulin resistance
Methods: 39 individuals with RA were matched with 39 individuals based on age, gender, race, and BMI. Exclusion criteria included diabetes, cardiovascular disease, recent medication changes, and prednisone use greater than 5 mg/d. All underwent measurements of disease activity (DAS-28), disability (HAQ-DI), glucose tolerance, plasma inflammatory cytokines, thigh CT imaging, physical activity (accelerometry), and vastus lateralis muscle biopsies. ELISAs were used to measure muscle (m) inflammatory markers: interleukin (mIL)-1β, mIL-6, mIL-8, tumor necrosis factor-alpha (mTNFα), and Toll-like receptor 4. Gene expression was measured in muscle from 5 matched case-control sets using Illumina Expression BeadChips. Differentially expressed genes were identified with Partek and used in pathway analyses performed with Ingenuity Pathway Analysis.
Results: Despite elevated systemic inflammation (C-reactive protein, IL-6, TNFα; P<0.05) in RA compared to controls, the only muscle cytokine with higher concentrations was mIL-6 (P=0.006). Nonetheless, in RA, higher mIL-1β and mIL-8 were correlated with higher DAS-28 (r=0.35, r=0.30, P<0.05). Higher mIL-1β and mIL-6 levels were associated with higher HAQ-DI (r=0.33, r=0.33, P<0.05). Higher concentrations of mIL-1β, mIL-6, and mIL-8 were associated with less exercise (r=-0.38, r=-0.40, r=-0.38, P<0.05), while higher mIL-1β and mIL-6 were related to less physical activity (r=-0.35, r=-0.33, P<0.05). Muscle cytokines had minimal correlation with insulin resistance and serum cytokines (P>0.05). Pathways with the most differences in muscle gene expression (P <0.05) had central molecules associated with the NF-kB and Ras/MapK pathways.
Muscle Inflammation Relationships in RA (n=39)
|
Variable |
mIL-1β |
mIL-6* |
mIL-8 |
mTNFα |
mTLR-4 |
|
Age (years) |
-0.308 |
-0.222 |
-0.003 |
0.013 |
-0.326† |
|
Body Mass Index (kg/m2) |
-0.339† |
-0.042 |
-0.273 |
0.024 |
-0.194 |
|
Disease Activity (DASESR-28) |
0.348† |
0.229 |
0.297† |
0.140 |
-0.005 |
|
Disability (HAQ-DI) |
0.325† |
0.329† |
0.190 |
0.085 |
0.119 |
|
Pain (Visual Analog Score) |
0.392† |
0.147 |
0.169 |
0.292† |
0.474† |
|
DMARD Use (Yes=1; No=0) |
0.210 |
-0.038 |
-0.071 |
0.031 |
0.079 |
|
Biologic Use (Yes=1; No=0) |
-0.330 |
-0.246 |
-0.369† |
0.208 |
0.008 |
|
Comorbidity Index |
0.262 |
0.168 |
0.115 |
0.166 |
-0.083 |
|
Insulin Sensitivity (x10-5 min-1/[pmol/L]) |
-0.094 |
-0.197 |
-0.190 |
-0.061 |
-0.175 |
|
hsCRP (mg/L) |
-0.033 |
0.202 |
0.066 |
0.113 |
-0.168 |
|
IL-1β (pg/mL) |
-0.137 |
0.008 |
-0.070 |
-0.071 |
-0.119 |
|
IL-6 (pg/mL) |
-0.006 |
-0.032 |
0.113 |
0.123 |
-0.097 |
|
IL-8 (pg/mL) |
0.140 |
-0.109 |
0.062 |
0.113 |
0.017 |
|
TNF-α (pg/mL) |
-0.230 |
-0.369† |
-0.149 |
0.020 |
-0.077 |
|
IL-18 (pg/mL) |
-0.240 |
-0.081 |
-0.121 |
-0.019 |
0.058 |
|
Thigh Muscle Density (Hu) |
0.155 |
-0.044 |
-0.095 |
0.057 |
0.295† |
|
Thigh subcutaneous adiposity (cm2) |
-0.092 |
0.310† |
-0.067 |
-0.106 |
-0.112 |
|
Exercise (min/w) |
-0.381† |
-0.400† |
-0.376† |
-0.051 |
-0.114 |
|
Physical Activity (METs/w) |
-0.354† |
-0.331† |
-0.260 |
0.099 |
-0.145 |
|
*P < 0.05 for comparison with matched controls †P < 0.05 for correlation coefficient |
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|
DASESR-28 = Disease activity score with 28 joint count and ESR=erythrocyte sedimentation rate; HAQ-DI= Health Assessment Questionnaire Disability Index; DMARD=Disease Modifying Anti-Rheumatic Drug; hsCRP = High sensitivity C-reactive protein; IL = Interleukin; Hu= Hounsfield units; TNF=Tumor Necrosis Factor; TLR-4=Toll-like receptor 4; Hu= Hounsfield units; METs= Metabolic Equivalents |
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Conclusion: While muscle inflammation is not a recognized feature of RA and does not relate to insulin resistance, higher levels of muscle inflammatory cytokines were related to worse disease activity, disability, and pain, as well as less physical activity. MapK and NF-kB are both important transcription factors that may activate signaling cascades resulting in higher levels of mIL-6 in RA patients. Further analyses are ongoing to better understand the role of skeletal muscle inflammation in RA.
To cite this abstract in AMA style:
Jessee R, Narowski R, Hubal M, Huebner J, Kraus V, Kraus W, Huffman K. Muscle Inflammation Relates to Disease Activity and Disability but Not Insulin Resistance in Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/muscle-inflammation-relates-to-disease-activity-and-disability-but-not-insulin-resistance-in-rheumatoid-arthritis/. Accessed .« Back to 2015 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/muscle-inflammation-relates-to-disease-activity-and-disability-but-not-insulin-resistance-in-rheumatoid-arthritis/