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Cervical Spine Research Society Focus Issue: Primary Research

Do Inflammatory Cytokines Affect Patient Outcomes After ACDF?

Karamian, Brian A. MD*,†; Levy, Hannah A. BS; Boere, Payton BS; Yalla, Goutham R. BS; Canseco, Jose A. MD, PhD*,†; Chang, Michael MD*,†; Divi, Srikanth N. MD*,†; Fang, Taolin MD, PhD; Millhouse, Paul W. MD; Lendner, Mayan BS; Hilibrand, Alan S. MD*,†; Vaccaro, Alexander R. MD, PhD, MBA*,†; Kepler, Christopher K. MD, MBA*,†; Markova, Dessislava Z. PhD; Schroeder, Gregory D. MD*,†

Author Information
doi: 10.1097/BSD.0000000000001318
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Abstract

Cervical spondylosis is estimated to be present in almost 90% of individuals over 60 years old.1 Degeneration of the intervertebral disc (IVD), vertebral body, facet joints, and ligamentous complexes within the cervical spine can lead to symptoms of radiculopathy and/or myelopathy.2,3 The sequalae of cervical spondylotic disease represents an important cause of disability, functional decline, and axial or radicular neck pain.2–4 While prudent to trial non-operative therapies, up to 30% of patients may fail pharmaceutical, corticosteroid injection, and physical therapy based treatments. Anterior cervical discectomy and fusion (ACDF) represents the gold standard treatment for such patients to provide foraminal or central decompression and stabilization for radicular and myelopathic conditions, respectively.5,6

While emerging research has explored the relationship between inflammatory markers and patient outcomes after orthopedic surgery, there is a paucity of evidence pertaining specifically to ACDF.7–10 Inflammatory pathways are known to play a critical role in processes including bone remodeling and nerve or spinal cord compression. In response to acute and chronic injury, neutrophils, macrophages, and T cells release proinflammatory cytokines such as interleukins (IL) and tumor necrosis factors (TNF) to stimulate cellular autophagy, senescence, and apoptosis.11 Elevated levels of cytokines (TNF-α, IL-1β, IL-6, IL-15, IL-17, IL-18) and c-reactive protein have been implicated in the pathogenesis of bone resorption and degeneration of cartilage in osteoarthritis.12,13 In spinal spondylotic disease, inflammatory cells and degenerating IVDs release TNFα, IL-1β, IL-6, IL-8, and IL-17 at elevated levels promoting cellular changes and matrix degradation resulting in disc space collapse, herniation, nerve/cord compression, pain generation, and ultimately functional disability.11,14–20 Emerging results suggest that elevated IL-6 may correlate with myelopathy severity and worse early functional outcomes after lumbar fusion.18,21 However, these preliminary findings require substantiation in the cervical spine and prompt further investigation into additional inflammatory cytokines.

The role of chronic inflammatory mediators and cytokines in the pathogenesis and severity of cervical spondylotic disease remains to be elucidated. Specifically, the potential correlation of preoperative serum inflammatory markers with preoperative and postoperative patient-reported outcome measures (PROMs) after ACDF has yet to be characterized. The purpose of this study is to evaluate the relationship between known mediators of inflammation [IL-6, IL-8, IL-1β, TNF-α, high-mobility group box-1 (HMGB1), and white blood cells (WBCs)] and preoperative cervical spine disease severity as well as functional improvement after ACDF.

MATERIALS AND METHODS

Patient Population

The study was approved by the institutional review board (IRB: No 14D.444). Patients over age 18 who underwent ACDF for cervical spondylosis with associated radiculopathy and/or myelopathy between 2015 and 2017 were recruited for study participation. Patients were excluded from enrollment if their surgery was performed for traumatic injury, malignancy, infection, or if they were diagnosed with systemic inflammatory or autoimmune diseases including but not limited to rheumatoid arthritis, lupus, chronic pulmonary disease, congestive heart failure, or diabetes. All willing participants were consented to preoperative blood donation for the purpose of accessing serum inflammatory markers. Patient demographics (age, sex, race, smoking status), surgical characteristics (preoperative diagnosis, number of levels fused), and PROMs were recorded at the time of preoperative consent. Duration of preoperative symptoms and preoperative opioid use were also noted.

Postoperative PROMs were collected by phone call or secure electronic survey at a minimum of 1-year follow-up. The primary result was preoperative and postoperative health-related quality of life outcomes including the neck disability index (NDI), visual analog scale (VAS) neck pain, VAS arm pain, and Short Form-12 (SF-12) with embedded Physical and Mental Component Scores (PCS and MCS). Patient specific delta (Δ) outcome scores were calculated by subtracting preoperative scores from postoperative scores, from which a recovery ratio (RR) was calculated (Δscore/optimal score–preoperative score).22 Achievement of minimum clinically important difference was determined according to established values for the PROMs studied: 2.6 points for VAS neck pain, 4.1 points for VAS arm pain, 17.3% for NDI, 8.1 points for SF-12 PCS, 4.7 points for SF-12 MCS.23

Sample Collection and Laboratory Analysis

Peripheral blood samples were collected preoperatively at the time of intravenous line placement by the anesthesia team. Venous blood (5–10 mL) was collected in nonheparinized vacuum sealed tubes and immediately centrifuged at 12,000 g for 10 minutes at 4°C. Subsequently, serum was aliquoted, flash frozen under liquid nitrogen, and stored at −80°C until biochemical analysis. The choice of serum cytokines assayed was representative of typical markers involved in inflammatory diseases. The concentration of serum cytokines including IL-6, IL-8, IL-1β, and TNF-α, were measured using V-PLEX Human Proinflammatory Panel II (4-Plex) according to the manufacturer’s instructions (Meso Scale Discovery, Rockville, MS). Samples were tested at a 2-fold dilution in duplicate using electrochemiluminescence on the SECTOR Imager 6000 instrument (Meso Scale Discovery). Concentrations of HMGB1 were measured with a commercially available enzyme-linked immunosorbent assays (ELISA) according to the manufacturer’s protocol (ST51011, Tecan).

Statistical Analysis

Descriptive statistical analysis compared patient demographics and outcomes through mean and SD, or number of occurrences and percent of total. Correlation between preoperative cytokines and both demographic parameters and PROMs was assessed with the Spearman rho coefficient. Spearman’s rho was interpreted as follows: 0−0.3 as negligible correlation, 0.3−0.6 as weak correlation, 0.6−0.8 as moderate correlation, 0.8−1 as strong to perfect correlation. All statistical analysis was performed with the Statistical Packages for the Social Sciences (SPSS) and R studio software (R Foundation for Statical Computing). A P-value <0.05 was considered statistically significant.

RESULTS

A total of 77 patients were prospectively identified and enrolled. Follow-up PROMs at a minimum of one-year after ACDF were available for 48 of the 77 study patients. The mean follow-up time was 22.83 (0.075) months. The average patient age was 52.7 years with 59.7% females and 40.3% males (Table 1). With regard to smoking status, 48.1% of patients were nonsmokers, 16.9% were current smokers, and 35.1% were former smokers (Table 1). The preoperative surgical indication was radiculopathy in 53.2% of patients, myelopathy in 16.9% patients, and myeloradiculopathy in 29.9% of patients (Table 1). The number of surgical levels fused ranged from one to four with 33.8% of patients receiving single-level fusions and 66.2% receiving multilevel fusions (Table 1).

TABLE 1 - Full Cohort Patient Demographic and Surgical Factors
Patient Parameter N=77, %
Age 52.7
Sex
 Female 59.7
 Male 40.3
Race code
 Caucasian 90.9
 African American 5.19
 Hispanic 2.60
 Asian 1.30
Diagnosis
 Radiculopathy 53.2
 Myelopathy 16.9
 Myeloradiculopathy 29.9
Smoker status
 Never 48.1
 Former 35.1
 Current 16.9
Levels fused
 Single-level 33.8
 Multilevel 66.2
Duration of preoperative symptoms
 <1 y 52.5
1 y 47.5
Preoperative opioid use
 Yes 23.7
 No 76.3

The overall mean preoperative cytokine levels were IL-6—1.02±0.70 pg/mL, IL-8—11.41±4.43 pg/mL, TNF-α—2.68±0.71 pg/mL, and HMGB1—1.61±2.16 pg/mL with mean WBC—6.91±2.51/ high powered field as displayed in Figure 1. Cytokines levels of IL-β were found to be below the assay’s detection limit and were excluded from subsequent analysis. The absolute concentrations of IL-6 and TNF-α were found to be weakly correlated with one another (ρ=0.479); however, no other preoperative cytokines were meaningfully correlated. Preoperative symptoms lasting <1-year were weakly correlated with elevation in HMGB1 (ρ=0.421). All other patient demographics exhibited negligible, if any, correlation with the preoperative inflammatory markers assessed (Table 2).

F1
FIGURE 1:
Serum levels of proinflammatory cytokines in patient cohort. IL indicates interleukin; TNF, tumor necrosis factor-α; HMGB1, high-mobility group box-1.
TABLE 2 - Correlation Between Patient Cytokines and Preoperative Demographics and PROMs
Patient Parameter IL-6, N=77 IL-8, N=77 TNF-α, N=77 HMGB1, N=49 WBC, N=75
Age 0.108 0.207 0.042 0.150 −0.031
Sex 0.029 −0.070 −0.046 −0.002 0.12
Race 0.045 −0.234 −0.210 −0.102 −0.154
Preoperative diagnosis 0.086 −0.033 0.019 0.074 −0.097
Smoking status 0.034 0.002 0.065 0.023 0.207
Number of levels fused 0.020 −0.248 −0.167 −0.088 0.017
Duration of preoperative symptoms −0.267 0.103 0.089 −0.421* −0.224
Preoperative opioid use −0.030 −0.039 −0.013 0.025 0.017
NDI 0.100 −0.142 −0.057 0.336* 0.317*
VAS arm −0.010 −0.014 0.061 0.085 0.189
VAS neck 0.035 −0.040 0.021 0.017 0.112
PCS −0.114 0.019 −0.036 −0.355* −0.167
MCS −0.075 0.044 −0.051 −0.298 −0.395*
*Indicates weak relationship.
HMGB1 indicates high-mobility group box-1; IL, interleukin; MCS, Mental Component Scores; NDI, neck disability index; PCS, Physical Component Scores; PROMs, patient-reported outcomes measures; TNF-α, tumor necrosis factor-α; VAS, visual analog scale; WBC, white blood cells.

Statistically significant preoperative to postoperative improvement was demonstrated for NDI (P=0.002), VAS arm (P <0.001), VAS neck (P <0.001), and PCS (P <0.001) scores. Lower preoperative PCS (ρ=0.355) and higher preoperative NDI (ρ=0.336) were weakly correlated with elevated HMGB1. Likewise, lower MCS (ρ=0.395) and higher NDI (ρ=0.317) preoperatively were weakly correlated with elevated WBCs. No other patient inflammatory markers correlated with the preoperative PROMs studied (Table 2). Delta MCS (ρ=0.306) and MCS RR (ρ=0.321) exhibited a weakly positive correlation with IL-6 (Table 3).

TABLE 3 - Correlation Between Preoperative Cytokines and Change in PROMs After ACDF
Change in PROM IL-6 IL-8 TNF-α WBC
Δ 0.072 0.039 −0.066 −0.219
NDI, N=43 RR −0.141 −0.078 0.075 0.082
MCID 0.032 −0.069 0.108 0.235
Δ 0.119 −0.163 −0.034 −0.251
VAS arm, N=44 RR −0.216 0.124 −0.016 0.143
MCID 0.046 0.096 0.000 0.103
Δ 0.051 −0.146 −0.069 −0.126
VAS neck, N=44 RR −0.229 0.014 −0.018 0.008
MCID −0.065 0.043 0.054 0.148
Δ −0.199 0.059 −0.095 0.180
PCS, N=47 RR −0.199 0.036 −0.086 0.192
MCID −0.232 0.154 −0.117 0.020
Δ 0.306* 0.091 0.098 0.201
MCS, N=47 RR 0.321* 0.125 0.104 0.208
MCID 0.298 0.219 0.240 0.190
*Indicates weak relationship.
ACDF indicates anterior cervical discectomy and fusion; IL, interleukin; MCID, minimum clinically important difference; MCS, Mental Component Scores; NDI, neck disability index; PCS, Physical Component Scores; PROMs, patient-reported outcomes measures; RR, recovery ratio; TNF-α, tumor necrosis factor-α; VAS, visual analog scale; WBC, white blood cells.

DISCUSSION

While the inflammatory cascade is known to play a critical role in the pathogenesis of acute and chronic spinal diseases, the relationship between patient cytokine levels and symptomatic disease severity or postsurgical outcomes is largely unknown. Accordingly, this investigation sought to determine whether serum inflammatory mediators correlated with cervical spondylotic disease severity or functional improvement after surgical intervention. The results of our study show that preoperative serum inflammatory marker concentrations including IL-6, IL-8, IL-1β, TNF-α, HMGB1, and WBCs were not significantly associated with preoperative PROMs or improvement in PROMs after ACDF.

Spondylotic disease is known to be mediated by the abnormal production of proinflammatory molecules secreted by discogenic cells (nucleus pulposus and annulus fibrosis), neutrophils, macrophages, and T cells.11,24 The spinal proinflammatory mediators include but are not limited to TNF-α, IL-1 α/β, IL-6, IL-17, IL-8, IL-2, IL-4, IL-10, IFN-γ, chemokines, and prostaglandin E2.11,25,26 Cytokines have intracellular and intercellular signaling function to link tissue-specific injury to local and systemic inflammation and pain responses.27 While cytokines represent byproducts of the inflammatory cascade and do not themselves directly degrade spinal tissues, elevated cytokine levels trigger cellular processes of autophagy, senescence, and apoptosis and are commonly implicated in the upregulation of matrix degradation enzymes.11,27 Increased expression of extracellular matrix metalloproteases-1 -3 -7 -9 and -13 and A disintegrin-like metalloprotease with thrombospondin type-1 motif (ADAMTS)-1, -4, -5, -9 and -15 are commonly associated with degeneration within the IVD (Fig. 2).28,29 The resultant structural defects increase the risk of disc herniation and can subsequently lead to immune cell activation and infiltration, nerve irritation, and new microvasculature and nociceptive fiber growth arising from the dorsal root ganglion (DRG).11,25,30 Among the inflammatory milieu, infiltrating cells release further cytokines and neurogenic factors (NGF, BDNF) associated with pain-generating cationic channels at the level of the DRG (Fig. 2).11,31,32 The disrupted spinal microenvironment (neovascularization and neoneuralization) and imbalance between extracellular matrix catabolic and anabolic activity lead to increased biomechanical stress because of the loss of disc height and inadequate absorption of axial loads.33 Subsequent increases in shear stress trigger bony remodeling and osteophyte formation leading to central or foraminal compression symptoms of myelopathy or radiculopathy, respectively.33

F2
FIGURE 2:
Inflammatory pathway of discogenic degeneration. BDNF indicates brain-derived neurotrophic factor; DRG, dorsal root ganglion; ECM, extracellular matrix; HMGB1, high-mobility group box-1; IL, interleukin; IFNγ, interferon; IVD, intervertebral disc; MMPs, matrix metalloproteinases; NGF, nerve growth factor; TNF, tumor necrosis factor-α; WBC, white blood cells.

The inflammatory cytokines IL-6, IL-8, IL-1β, TNF-α, HMGB1 investigated in the present study were selected because of their demonstrated upregulation in animal models and human tissues corresponding to degenerative disc disease, myelopathy, or radiculopathy.15,16,19,34,35 Multiple studies have evaluated the cytokine profiles of degenerative IVDs specimens from patients undergoing spinal fusion surgery.16,34,36 Degenerating IVDs were associated with increased expression IL-6, IL-8, IL-1β, and RANTES/CCL5 in culture.16,34,36 Specifically, IL-1β and RANTES were found to be elevated in painful IVDs and IL-1β correlated with the pathologic severity of disc degeneration.34 In addition, human IVD cells treated with IL-1β resulted in upregulation of matrix-degrading enzymes.16

Animal and human studies have also investigated the cytokine concentrations in cerebrospinal fluid (CSF) and serum of patients with cervical myelopathy.18,19,37,38 In a rat myelopathy model, infusion of IL-6 resulted in motor dysfunction and mechanical allodynia threshold decline.18 Likewise, IL-6 and IL-8 were shown to be elevated in the CSF of patients with myelopathy compared with control groups, scaling with the severity of spinal cord compression.18,19,37,38 IL-6 concentrations have also been shown to be elevated in the serum of myelopathy patients.18

While the understanding of human cytokine profiles of patients with isolated radiculopathy is more limited, robust animal research studies have measured inflammatory markers in the setting of nerve root injury.35,37,39,40 Recombinant TNF-α applied directly to the rat DRG, to mimic disc herniation, resulted in apoptosis of the DRG cellular nuclei.35 Furthermore, animal models of nerve root ligation led to upregulation of IL-1 α/β, IL-6, IL-10, and TNF-α in spinal tissues, in which increased magnitude of ligation correlated with greater expressions,39 which may explain why increased CSF concentrations of IL-6 were detected in patients with lumbar radiculopathy.37

The role of HMGB1 in degenerative disc disease, myelopathy, and radiculopathy is yet to be elucidated. However, emerging evidence suggests that HMGB1 is important in spinal cord injury.41,42 In astrocyte culture, HMGB1 is shown to upregulate aquaporin expression promoting cellular swelling after an oxygen-glucose deprivation/reoxygenation process mimicking acute spinal cord compression.41 In addition, injection of recombinant HMGB1 into the mouse spinal cord demonstrated co-localization with macrophages and focal areas of neuronal killing.42 WBCs were also examined in our study because they both secrete and respond to the abovementioned cytokines (IL-6, IL-8, IL-1β, TNF-α, HMGB1, among others) to enable the inflammatory cascade.11,15,43

Despite extensive research evaluating inflammatory pathways involved in spinal spondylosis, there is a paucity of evidence to correlate inflammatory markers to clinically relevant outcomes. Previous investigations have shown that increased IL-6 serum and discal expression is associated with increased myelopathy symptom severity as well as postoperative back pain and disability, respectively.18,21 In a study of elderly women with acute lower back pain, plasma elevations of IL-6 were associated with depressive symptoms and pain while elevations of TNF-α were associated with disability and pain.44 However, there is also evidence to suggest that IL-6 and TNF-α concentrations may not be significantly associated with pre- or postoperative outcomes as studies have demonstrated that preoperative functional status (Japanese Orthopaedic Association Scale) in myelopathy and VAS Back pain in degenerative disc disease did not correlate with patient serum and intradiscal IL-6 concentrations, respectively.21,37 Furthermore, cervical myelopathy and lumbar radiculopathy symptom durations were not found to correlate with IL-6 expression.18,37 Lastly, anti-IL-6 and anti-TNF-α receptor intradiscal injections to target discogenic back pain have demonstrated minimal and transient efficacy, underscoring the limited therapeutic role of cytokine blockade in improving PROMs.45,46

The present work demonstrates no significant correlations between serum cytokine concentrations and patient demographics, preoperative PROMs, or postoperative change in PROMs. In addition, our study failed to find an association between preoperative symptom duration and cytokine expression. The absence of correlation between preoperative PROMs and cytokines suggests that inflammatory markers may not be able to meaningfully predict pain, disability, or functional status for these patients. Furthermore, preoperative cytokine levels failed to associate with any PROM improvement metrics (delta, RR, minimum clinically important difference), demonstrating that cytokines may not play a significant role in long-term postoperative recovery. While the presented findings disagree with previous literature regarding the relationship between IL-6 and TNF-α and poor clinical outcomes, notable differences in cohort selection and methodologies necessitate further investigation. The cytokine expressions in patient discogenic tissue, CSF, and blood serum may not be comparable.18,21,37 Inflammatory markers are associated with both local and systemic responses, where relative elevations in the serum may have been attenuated for local responses.47 Moreover, the comparative profiles of patient cytokines have been demonstrated to vary significantly based on preoperative diagnosis, which may account for the discrepancy between our cohort and the positive findings in the literature.15,20 Even though preoperative diagnosis (radiculopathy, myelopathy, myeloradiculopathy) was not found to correlate meaningfully with cytokine concentrations in our study, the disease-specific variation in inflammatory mediators and the potential cofounding effects of preoperative diagnosis on PROMs cannot be ignored.15,20 Lastly, with regard to postsurgical PROMs, previous literature has associated IL-6 and clinical outcome improvement at an earlier 6-month follow-up.21 In the present investigation we assessed PROMs at 1-year to 2-year follow-up, which may be more reflective of long-term clinical outcomes.

This study is not without limitations. The patients lost to postoperative follow-up introduce a selection bias that may alter the relationship between PROM improvement and cytokine levels. The small patient cohort size limited stratification by preoperative diagnosis, a factor shown to alter cytokine profiles. With regard to cytokine measurement, the correlation between IL-1β and patient outcomes could not be assessed because the IL-1β concentration was below the detection limit of the manufactures assay, where further efforts to concentrate the samples may have led to more reliable detection. In addition, given the limited number of patients with HMGB1 measurement, correlation of these markers with PROM improvement was not possible. Finally, the interpatient variability in cytokine concentrations is not adequately controlled because no normative data exists regarding serum cytokine concentrations in patients with cervical spondylosis.

CONCLUSIONS

Preoperative cytokine levels demonstrated minimal correlation with preoperative symptoms or clinical improvement after ACDF. The findings suggest that the profiling of patient cytokines has limited utility in predicting the effects of surgical intervention or guiding management in patients with cervical spondylotic disease.

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Keywords:

serum cytokines; inflammatory markers; anterior cervical discectomy and fusion; clinical outcomes; patient-reported outcome measures

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