Research Paper
Tumor necrosis factor inhibitor therapy in ankylosing spondylitis: differential effects on pain and fatigue and brain correlates Qi Wua, Robert D. Inmanb,c,d, Karen D. Davisa,c,e,*
Abstract Ankylosing spondylitis is associated with back pain and fatigue and impacts mobility but can be treated with tumor necrosis factor inhibitors (TNFi). The differential effects of TNFi treatment on multiple symptoms and the brain is not well delineated. Thus, we conducted a 2-part study. In study 1, we conducted a retrospective chart review in 129 ankylosing spondylitis patients to assess TNFi effects on pain, fatigue, motor function, mobility, and quality of life (QoL). After at least 10 weeks of TNFi treatment, patients had clinically significant improvements (.30%) in pain (including neuropathic pain), most disease and QoL factors, and normalized sensory detection thresholds. However, residual fatigue (mean 5 5.3) was prominent. Although 60% of patients had significant relief of pain, only 22% of patients had significant relief of both pain and fatigue. Therefore, the preferential TNFi treatment effect on pain compared with fatigue could contribute to suboptimal effects on QoL. Part 2 was a prospective study in 14 patients to identify TNFi treatment effects on pain, fatigue, sensory and psychological factors, and brain cortical thickness based on 3T magnetic resonance imaging. Centrally, TNFi was associated with statistically significant cortical thinning of motor, premotor, and posterior parietal regions. Pain intensity reduction was associated with cortical thinning of the secondary somatosensory cortex, and pain unpleasantness reduction was associated with the cortical thinning of motor areas. In contrast, fatigue reduction correlated with cortical thinning of the insula, primary sensory cortex/inferior parietal sulcus, and superior temporal polysensory areas. This indicates that TNFi treatment produces changes in brain areas implicated in sensory, motor, affective, and cognitive functions. Keywords: Gray matter, Pain, Fatigue, Biologics, TNF
1. Introduction Ankylosing spondylitis (AS) is a debilitating rheumatic condition characterized by pain, fatigue, and reduced mobility that can severely affect quality of life (QoL) and work-related activity. Conventional symptom management, such as nonsteroidal antiinflammatory drugs and traditional disease-modifying antirheumatic oral drugs, has only modest efficacy. However, up to 60% of patients treated with tumor necrosis factor inhibitors (TNFi) have greatly improved serological parameters (ie, erythrocyte sedimentation rate, C-reactive protein) and radiological outcomes5,14,18,26,34 and improvement in pain and indicators of disease activity.17,20 Despite these positive outcomes of TNFi treatment for AS, the brain mechanisms underlying TNFi effects on pain and fatigue are not known. If fatigue correlates well with pain in patients with AS, then fatigue would be expected to be comparably improved with Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. a
Division of Brain, Imaging and Behaviour-Systems Neuroscience, Toronto Western Research Institute, Toronto, ON, Canada, b Division of Rheumatology, Toronto Western Hospital, Toronto, ON, Canada, c Institute of Medical Science, University of Toronto, Toronto, ON, Canada, Departments of d Medicine and, e Surgery, University of Toronto, Toronto, ON, Canada *Corresponding author. Address: Toronto Western Hospital, Room MP14-306, 399 Bathurst St, Toronto, ON M5T 2S8, Canada. Tel.: (416) 603-5662; fax: (416) 603-5745. E-mail address: [email protected] (K. D. Davis). PAIN 156 (2015) 297–304 © 2015 International Association for the Study of Pain http://dx.doi.org/10.1097/01.j.pain.0000460310.71572.16
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reduction of pain. However, this may not be the case. Previous studies report a considerable residual fatigue in patients with AS after treatment with TNFi37 regardless of the amount of pain relief.26 Our recent brain imaging investigation of the central mechanism of fatigue in AS indicates that pain and fatigue have differential effects on the brain; fatigue more strongly impacting motor and attentional networks40 than areas more classically implicated in pain perception.7 The aim of this study was to examine the differential effect of TNFi treatment on symptom relief in patients with AS with focus on pain and fatigue. Because there are distinct central mechanisms associated with pain and fatigue, we hypothesized that the relief of pain and fatigue by TNFi might have different trajectories. To test these hypotheses, we performed 2 studies: (1) a retrospective review of patients with AS to determine the efficacy of TNFi treatment on pain and fatigue and (2) a prospective brain imaging study in patients with AS to determine the brain plasticity associated with TNFi in general and specifically the brain effects related to the change in pain and fatigue after TNFi treatment.
2. Methods 2.1. Study participants Two study designs were used as follows: (1) a cross-sectional clinical assessment in 129 TNFi-treated patients with AS and (2) a prospective brain imaging/psychophysical assessment in 25 additional patients with AS and age/sex-matched controls. All patients were recruited from the Toronto Western Hospital AS www.painjournalonline.com
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Clinic where they received a standard treatment regimen of TNFi biologics for at least 10 weeks (a stable blood concentration is reached by this time point). In standard protocols and dosing as recommended by the ASAS/EULAR recommendations for the management of AS, TNFi biologics were given to patients.4 Sexand age-matched healthy subjects were recruited from the Toronto Western Research Institute community of staff and students, and they provided informed written consent to this study that was approved by the University Health Network Research Ethics Board. For study 1, clinical variables from 129 patients with AS were retrieved from the clinic’s AS database using the following inclusion criteria: (1) a diagnosis of AS according to the modified New York criteria,35 (2) current TNFi treatment, and (3) identifiable pretreatment and posttreatment time points and corresponding data. For study 2, an additional 25 patients with AS provided informed written consent for the psychophysics and magnetic resonance imaging (MRI) experiments and were recruited from the clinic using the following inclusion criteria: (1) fatigue severity scale (FSS) .3, (2) total back pain (TBP) .3 of 10 on a categorical rating scale from 0 to 10, (3) a stable dose of analgesics, and (4) not on biologics at the time of the study. Additional general inclusion criteria for all participants in the prospective study were age between 18 and 60 years, without severe psychiatric or neurological conditions (ie, depression, fibromyalgia) based on history and clinical interview, no history of diabetes, no major surgery within the past 2 years, and considered to be appropriate for brain MRI. Of the 25 patients with AS enrolled, 11 were excluded from the final longitudinal analysis for TNFi effects (8 of these 11 patients did not complete the TNFi treatment, 2 patients who received treatment were lost in follow-up, and 1 patient had MRI scans acquired with different parameters). 2.2. Clinical and psychophysical assessments and brain imaging For study 1, the AS database was used to identify demographic and clinical variables related to the efficacy of the TNFi characterized by disease-related variables such as TBP by a numerical rating scale, FSS, Bath AS disease activity, function, and metrology indices (bath ankylosing spondylitis disease activity index [BASDAI], bath ankylosing spondylitis function index [BASFI], and BASMI, respectively),36 and ASQoL. A clinically significant improvement threshold was set at “30% improvement” from baseline, which is a standard outcome measure in many chronic pain conditions including low back pain and osteoarthritis.9,23 For study 2, patients with AS completed questionnaires (including Pain Catastrophizing Scale31 [PCS], Affect Intensity Measure8 [AIM], painDETECT,11 and FSS19) and underwent psychophysic testing to determine sensory thresholds, and a 3T MRI scan, at 2 time points: before and 4 months after the start of TNFi treatment. Age- and sex-matched healthy controls also completed the PCS and AIM and underwent the psychophysical and MRI assessment. Patients with AS were asked to rate their average TBP they had over the past week on a categorical scale of 0 to 10. A modified, 9-item 10-point FSS was used to determine the severity of fatigue.19 The PCS (range 0-5231 and the 40-item 6-point scale AIM8 were used to assess the cognitive/affective functions as previously described.40 The painDETECT Questionnaire11 was used to determine the neuropathic component of AS pain. As described in our previous report,39 a standard psychophysics assessment was conducted to determine the mechanical and
thermal thresholds of the feet. Von Frey filaments (OptiHair2; Marstock Nervtest, Schriesheim, Germany) were used to determine mechanical thresholds (set of 12 monofilaments [contact surface, ;0.4 mm], bending forces from 0.25 to 512 mN). Subjects were instructed to close their eyes during the testing. Monofilaments were applied in ascending order, and subjects instructed to identify when they felt a sensation. Mechanical detection and pain thresholds in each subject were defined as the force of the finest filament to be detected and evoke pain, respectively. A computercontrolled Peltier device (TSA-II NeuroSensory Analyzer; Medoc Ltd, Ramat Yishai, Israel) with a 30 3 30-mm probe was used to deliver thermal stimuli on the skin to delineate thermal thresholds. From a baseline temperature of 32˚C, the probe temperature changed at a rate of 0.5˚C/s until the subject pressed a button to indicate the detection of sensation being assessed. The range of the delivered temperatures was between 0˚C and 50˚C. Three trials for cool and warm detection and 5 trials for cold pain and heat pain were run. Individual thresholds were calculated as the average of 3 trials for thermal detection and the last 4 of the 5 trials for thermal pain. 2.3. Magnetic resonance imaging data acquisition Study participants were scanned with a 3T GE MRI scanner equipped with an 8-channel phased-array head coil. T1weighted anatomical scans were acquired with the following parameters: 3D IR-FSPGR sequence; 180 axial slices, slice thickness 1 mm, matrix 256 3 256; 1 3 1 3 1 mm voxels; flip angle 5 15˚; TE 5 3 milliseconds; TI 5 450 milliseconds; and TR 5 7800 milliseconds. Brain MRI image processing and cortical thickness analyses (both cross-sectional and longitudinal) were done in Freesurfer 5.2, a standard commonly used software package (http:// freesurfer.net/). The imagewise significance was a corrected level of P , 0.05 (derived from 87 contiguous voxels for the region of interest [ROI] approach and 98 contiguous voxels for the wholebrain approach; 5000 iterations of Monte Carlo simulations). Sigmaplot (version 12; Systat Software, Inc, San Jose, CA) was used to deal with nonimaging data. The specific imaging methodological details are described below. All T1-weighted images were fed into a standard preprocessing pipeline including intensity normalization, skull stripping, separation of the hemispheres, and gray matter segmentation. For the longitudinal analysis, an additional “base step” was needed (after the above “cross” step), where an unbiased median image for each patient subject was established as the withinsubject template onto which images from the 2 time points were registered. Each time point, then, was processed “longitudinally” using the information from both the “cross” and “base” steps.25 Finally, a Gaussian smoothing kernel of 4-mm full-width half maximum was applied to the preprocessed images. Cortical thickness (for the cross-sectional analysis) or the difference in cortical thickness (for the prospective analysis) was extracted and modeled into voxelwise general linear models. T1-weighted images from a total of 22 AS patients at baseline were used to establish the whole-brain cortical correlates with either pain intensity ratings or pain unpleasantness ratings. Three of these patients were excluded from this analysis because of technical imaging issues and/or poor images. Cortical regions (Brodmann Areas) found to be associated with AS pain were identified with the cortical parcellations map implemented into FreeSurfer (Population-Average, Landmark- and Surface-based Brodmann Area Mask [PALS-B12]) (see http://freesurfer.net/), and used to create a ROI mask to guide subsequent longitudinal analysis in the 14 patients.
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2.4. Statistical analysis Clinical data from study 1 and nonimaging data from study 2 were analyzed with Statistical Package for the Social Sciences v16.0 (SPSS Inc, Chicago, IL). A Pearson normality test was run to determine whether data exhibited a normality distribution and whether parametric or nonparametric tests should be followed. Student t tests were used to compare baseline demographic variables and disease-related variables from study 1 and study 2. Depending on the data distribution, either paired t test or Wilcoxon signed-rank test was used to compare paired nonimaging data before and after the TNFi treatment, and either Pearson product–moment correlation or Spearman’s rank order correlation was used for bivariate correlation analyses. Forward stepwise selection was performed in multivariate general linear modeling. Correlation of cortical thickness values (extracted from FreeSurfer) with clinical variable was analyzed using SPSS, and correlation graphs were also generated using SPSS.
3. Results The patients in study 1 and study 2 did not differ in baseline demographic variables, such as age and sex composition, and the main disease-related variables, such as TBP and FSS (all P . 0.05; Table 1).
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DOMJAN (lateral spinal mobility to the left), and ASQoL (all P , 0.001; paired t test; Table 1 and Fig. 1). The improvements in pain and disease activity, function, and metrology index were a .30% reduction compared with the baseline. However, the improvement in fatigue was only 19.7% of baseline values (Fig. 1). The % reductions in TBP and FSS were significantly correlated % (r 5 0.422, P , 0.001; Pearson product–moment correlation test; Fig. 1). Although 60% of patients had .30% pain reduction, only 35% of patients had .30% fatigue reduction and only 20% of the patients had .30% improvement in both pain and fatigue. After treatment, AS patients still suffered a considerable amount of fatigue (residual FSS 5 5.3 6 2.7). We also found that 57% of AS patients had a residual FSS score .5, whereas only 24% of them had a residual FSS score ,3, which was slightly improved compared with the baseline where 72% of patients had an FSS score .5 and 11% with an FSS score ,3. Both TBP and FSS significantly correlated with ASQoL at both time points (all P , 0.001, Spearman’s rank order correlation). After the treatment, the residual fatigue became the main source of the posttreatment ASQoL accounting for 60.4% of variance (TBP for an addition of 7.1%; stepwise multiple regression). This contrasted the baseline scenario, where TBP was the main ASQoL determinant accountable for 35.2% of variance and FSS as the secondary adding another 16.9% of variance.
3.1. Efficacy of tumor necrosis factor inhibitors in AS patients: a cross-sectional survey
3.2. Effects of tumor necrosis factor inhibitors on peripheral sensory processing in ankylosing spondylitis patients: a longitudinal study
The average duration of TNFi treatment in study 1 was 59.3 weeks (range, 10-256 weeks). The TNFi significantly improved most major AS-related variables, including TBP, FSS, BASDAI, BASFI, left
To understand how TNFi treatment changes the quality and potential neuropathic contribution to back pain, we administrated the painDETECT questionnaire to the patients in study 2. After TNFi
Table 1
Ankylosing spondylitis patient demographics and sensory thresholds. Study 1 (N 5 129) Before Age, y Sex TBP FSS BASDAI BASFI QoL DOMJAN L DOMJAN R PCS AIM painDETECT MD L, mN MD R, mN MP L, mN MP R, mN CD L, ˚C CD R, ˚C CP L, ˚C CP R, ˚C WD L, ˚C WD R, ˚C HP L, ˚C HP R, ˚C
Study 2 (N 5 14) After
43.6 6 11.4 34 female/95 male 6.7 6 2.5 6.6 6 2.5 6.4 6 2.0 5.6 6 2.4 11.7 6 4.9 11.9 6 6.1 13.4 6 6.4 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA
3.7 6 2.8* 5.3 6 2.6* 3.6 6 2.2* 3.5 6 2.7* 7.3 6 5.9* 13.2 6 6.1* 13.5 6 6.2 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA
Controls
Before
37.2 6 10.2 NA NA NA NA NA NA NA 13.7 6 10.6 3.6 6 0.4 NA 1.6 6 1.4 1.1 6 0.6 95.7 6 95.6 82.1 6 86.6 29.3 6 1.8 29.6 6 1.6 15.1 6 10.3 15.7 6 10.1 36.5 6 3.1 35.3 6 1.9 44.9 6 2.7 44.2 6 3.7
After 37.6 6 11.9 3 female/11 male
6.0 6 1.7 6.5 6 2.8 NA NA NA NA NA 23.7 6 12.9 3.9 6 0.6 12.9 6 7.4 2.8 6 2.6 2.5 6 2.6 78.3 6 142.8 83.4 6 138.8 27.6 6 3.5 28.2 6 1.9 14.2 6 8.7 15.5 6 8.4 37.9 6 4.0 36.8 6 2.2 45.7 6 2.5 44.9 6 10
3.8 6 2.5† 5.9 6 3.2 NA NA NA NA NA 18.5 6 12.9† 3.9 6 0.5 8.9 6 6.0 2.4 6 2.7 1.5 6 1.3† 79.1 6 131.1 80.6 6 139.5 27.7 6 2.4 28.1 6 2.4 15.0 6 9.1 14.2 6 9.8 36.9 6 3.2† 37.2 6 3.3 46.1 6 2.9 45.3 6 3.8
Values are represented as mean 6 SD. No other significant comparisons were found in any parameters in studies 1 and 2. There was no difference between study 1 and 2 in age, sex composition, baseline TBP or baseline FSS. * P , 0.001 (paired t test) compared with the baseline in study 1. † P , 0.05 (paired t test) compared with the baseline in study 2. AIM, Affect Intensity Measure; BASDAI, bath ankylosing spondylitis disease activity index; BASFI, bath ankylosing spondylitis function index; CD, cold detection threshold; CP, cold pain threshold; DOMJAN, DOMJAN score of lateral spinal mobility; FSS, fatigue severity scale; HP, heat pain threshold; L/R, left/right foot; MD, mechanical detection threshold; MP, mechanical pain threshold; NA, not available; PCS, Pain Catastrophizing Scale; QoL, quality of life; TBP, total back pain; WD, warm detection threshold.
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Figure 2. Effect of TNFi on painDETECT scores in AS patients (study 2). Individual painDETECT scores were obtained before and after treatment with a TNFi. The dotted line depicts the painDETECT level of 12, indicating a possible neuropathic component. Fourteen patients in study 2 were included in the analysis. AS, ankylosing spondylitis; TNFi, tumor necrosis factor inhibitor.
3.3. Baseline features associated with pain and fatigue relief Figure 1. Efficacy of TNFi in pain and fatigue relief in AS patients (study 1). Top left panel: TNFi significantly reduced the TBP (P , 0.001, paired t test), which was .30% reduction of the baseline and was therefore of clinical significance as well. Top right panel: TNFi statistically significantly reduced the FSS (P , 0.001, paired t test); however, this was not of clinical significance as the degree of improvement was ,30% reduction of the baseline. Bottom panel: the percentage improvements in TBP and FSS were significantly correlated; only a small portion of patients (plots of the top right corner) had clinical improvements in both TBP and FSS (.30% of reduction of the baseline, indicated by dotted lines). AS, ankylosing spondylitis; FSS, fatigue severity scale; TBP, total back pain; TNFi, tumor necrosis factor inhibitor.
treatment, the group painDETECT scores were significantly reduced (P , 0.05, paired t test, Table 1). Reduced scores occurred for patients who had baseline scores above and below the level of 12 that indicates a likelihood of neuropathic pain component. Specifically, of the 7 patients with baseline painDETECT scores above 12, 5 had reduced scores after TNFi treatment (3 below 12). Of the 7 patients with baseline painDETECT scores below 12, 5 had decreased scores after treatment (Fig. 2). The effect of treatment on pain, FSS, and PCS scores for each patient after treatment is provided in Table 2. To investigate how the treatment affects sensory thresholds, we determined psychophysical thresholds and found that, compared with the baseline values, the mechanical detection threshold on the right foot was significantly lower after the treatment (P , 0.05, Wilcoxon signed-rank test; Table 1) and the warm detection threshold on the left foot was significantly lower after the treatment (P , 0.05, paired t test; Table 1). No other sensory thresholds were altered by the treatment (Table 1).
To determine whether any baseline clinical variables (TBP, FSS, BASDAI, BASFI, or ASQoL) could account for the efficacy of the TNFi treatment (in terms of percent relief in TBP or fatigue), we included all these variables in multivariate models using the forward stepwise approach. For the patients in study 1, the percent relief in TBP was related to the baseline TBP (r 5 0.451, P , 0.05) and BASDAI (r 5 0.497, P , 0.05), and the percent relief in fatigue was related to the baseline FSS (r 5 0.296, P , 0.01). Furthermore, we asked whether any baseline cognitive and sensory variables were associated with the percent reduction in pain or fatigue using data from study 2. We found that the percent relief in back pain intensity was correlated with the baseline AIM (intensity of positive emotion, r 5 0.655, P , 0.01; Pearson product–moment correlation test), the percent relief in FSS was correlated with the baseline mechanical detection threshold of the left foot (r 5 20.543, P , 0.05; Pearson product–moment correlation test), and the residual fatigue was correlated with the mechanical detection thresholds of both feet (left, r 5 0.633, P , 0.05; right, r 5 0.616, P , 0.05; Pearson product–moment correlation test). 3.4. Ankylosing spondylitis pain–related cortical thickness abnormalities and the effects of tumor necrosis factor inhibitors In 22 AS patients not yet treated with TNFi, we found that TBP was positively correlated with cortical thickness of the temporoparietal junction (TPJ) and negatively correlated with cortical thickness of the left primary and supplementary motor area (M1 and SMA), anterior mid-cingulate cortex and lingual gyrus, the
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Table 2
Self-reported pain-related ratings in patients with AS in study 2. ID/Age/Sex
Interval, wk*
Before TNFi 1/22/M 2/50/M 3/36/F 4/50/M 5/60/M 6/37/M 7/34/M 8/31/M 9/30/M 10/22/F 11/37/M 12/27/M 13/55/M 14/26/F After TNFi 1/22/M 2/50/M 3/36/F 4/50/M 5/60/M 6/37/M 7/34/M 8/31/M 9/30/M 10/22/F 11/37/M 12/27/M 13/55/M 14/26/F
17 20 47 18 19 15 14 34 33 30 35 19 19 18
PCS
AIM
TBP
painDETECT
FSS
47 28 21 44 1 5 36 25 12 23 24 26 20 20
4.7 3.7 4 4.8 3.9 3.1 4.7 3.9 4.1 4.6 3.3 3 3 4.1
8 7 6 6 7 4 7 5 7 8 6 3 7 3
24 17 4 11 21 7 13 11 14 25 3 18 3 9
10 4.1 8.6 9.7 6.9 1.7 10 5.3 5.2 8.1 4.4 8.7 1.8 6.6
38 16 21 47 2 7 14 28 26 21 16 11 8 4
5.1 4.1 4.2 4.2 4.1 3.2 4.6 3.3 4.5 4.6 3.2 3.5 3.4 3.8
4 6 8 5 7 1 1 1 6 2 6 3 2 1
11 10 1 8 21 4 5 14 13 18 7 5 1 6
9.4 8.6 8.6 9.6 6.8 0.7 2 8.9 7.7 7 4.4 5.7 1.2 2.9
* Represents the interval between the initiation of TNFi treatment and the follow-up MRI scan. AIM, Affect Intensity Measure; AS, ankylosing spondylitis; FSS, fatigue severity scale; MRI, magnetic resonance imaging; PCS, Pain Catastrophizing Scale; TBP, total back pain; TNFi, tumor necrosis factor inhibitor.
right secondary sensory cortex (S2) and fusiform, and bilateral inferior parietal lobe (Fig. 3, Table 3). These areas were used to generate an ROI brain mask to represent AS back pain. For the patients who were scanned after TNFi treatment, we found cortical thinning in 3 regions within the ROI mask: the left M1/ SMA, the left inferior parietal sulcus, and the right premotor area (Table 3 and Fig. 4). 3.5. Cortical correlates of the tumor necrosis factor inhibitors–induced pain and fatigue relief We next correlated for each patient, the percent TBP relief with changes in cortical thickness at the whole-brain level. This analysis revealed that the percent reduction TBP was correlated with cortical thinning of the right S2 and with the cortical thickening of the left orbitofrontal cortex, whereas the percent fatigue relief was correlated with cortical thinning of the left insula, the right primary sensory cortex/inferior parietal sulcus border area, and bilateral superior temporal polysensory areas (Figs. 5 and 6, Table 3).
4. Discussion The present data demonstrate that TNFi has a greater effect on relieving back pain than fatigue; with only a small portion of AS patients reporting improvements in both pain and fatigue. This finding highlights an important limitation of TNFi for treatment of AS given that the residual fatigue can be a major contributor of
Figure 3. Cortical areas in AS related to baseline TBP. Whole-brain analysis of cortical areas associated with TBP at the baseline AS patients was overlaid onto the average brain. Blue clusters, negative correlations of cortical thickness with TBP; the red cluster, a positive correlation. All involved areas were built as the ROI mask for further longitudinal analyses. aMCC, anterior mid-cingulate cortex; IPL, inferior parietal lobule (containing the temporoparietal junction); Lingual, lingual gyrus; L/R, left and right hemispheres; M1, primary motor cortex; SMA, supplementary motor area; S2, secondary somatosensory cortex; TBP, total back pain.
poor QoL. The data also suggest that baseline factors, such as pain, fatigue, disease severity, and positive emotion strength, may contribute to the effects of pain and fatigue relief. Furthermore, we found other effects of TNFi including attenuated neuropathic pain, reversal of sensory loss and improved lateral spinal mobility, and altered cortical thickness. 4.1. Clinical effects of tumor necrosis factor inhibitors Our retrospective chart review confirms previous observations about the effectiveness of TNFi in a wide range of disease-related variables in AS patients,3,5,13,14,18,34 including BASDAI, BASFI, TBP and QoL, although it should be noted that a limitation of this study was that it was not formally placebo controlled. It has been shown that pain and fatigue, together with sleep disturbance and stiffness, are the QoL concerns in AS patients.38 Therefore, we focused on the association of pain relief with the impact of TNFi on fatigue and found that only a modest proportion (22%) of patients reported significant improvement in both these key areas. Although differences in sensitivity across pain and fatigue scales may explain why the effect of TNFi was clinically significant for pain but not for fatigue, these findings are somewhat at odds with previous findings. Some studies report significant and satisfactory fatigue relief by TNFi.3,6,13 Our earlier clinical trial in pilot subjects showed that significant relief of fatigue occurs rapidly after 6 weeks of TNFi treatment,30 although this significance became borderline (P 5 0.0299) after 14 weeks on TNFi. However, other studies report poor responsiveness of fatigue to TNFi.26,37 In our current survey of patients on long-term TNFi (average 59 weeks), patients only had a modest 20% relief in fatigue. Additional analysis showed that 57% of patients were still fatigued (FSS . 5) and that the residual fatigue became the primary QoL factor after the treatment. Several factors might account for this discrepancy regarding TNFi and fatigue. First, most studies that report good responsiveness of fatigue to TNFi use a single-item scale for fatigue measure, which might not be as accurate as the multi-item FSS used in this study.10 Second, the duration of TNFi treatment in our study was much longer than
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Table 3
Cortical areas associated with TNFi, TBP, and fatigue in patients with AS. BA
Region Whole-brain analysis: correlation with TBP before TNFi 4/6 40 39 32 18 20 37 39 41/43 ROI analysis: cortical thickness changes after TNFi* 4/6 7/19 6 Whole-brain analysis: percent TBP relief after TNFi 11 43 Whole-brain analysis: percent fatigue relief after TNFi 22/39 2/7 22 22
T value
Size (voxels)
50 35 31 35 2 212 3 41 19
25.123 3.383 23.717 22.939 23.198 23.631 23.555 24.214 23.588
113 102 107 105 142 163 99 118 143
210 270 24
55 29 47
24.526 23.257 23.065
108 93 93
224 54
27 213
212 19
3.218 23.687
99 103
232 250 31 63 57
221 249 239 226 228
10 6 47 3 29
24.735 23.714 24.079 23.809 25.167
145 141 144 119 127
Peak (TAL, mm) x
y
z
SMA/M1 IPL/TPJ IPL/TPJ aMCC Lingual gyrus Fusiform Fusiform IPL S2
224 249 240 211 29 37 50 39 45
210 256 258 21 272 232 255 264 220
M1/SMA IPS PMA
217 223 22
OFC S2
Insula STPa S1/IPS STPa STPa
Negative x coordinates indicate left brain. * Corresponding cortical thickness (mean, mm) in patients at both time points and in matched healthy subjects are provided as follows: the left BA4/6 cluster (before, 2.5; post, 2.3; control, 2.6); the left BA7/19 cluster (before, 2.1; post, 2.0; control, 2.2); and the right BA6 cluster (before, 2.5; post, 2.3; control, 2.5). aMCC, anterior mid-cingulate cortex; AS, ankylosing spondylitis; BA, Brodmann area; IPL, inferior parietal lobe (part of TPJ); IPS, inferior parietal sulcus; M1, primary motor cortex; OFC, orbitofrontal cortex; PMA, premotor area; ROI, region of interest; S1/S2, primary/secondary somatosensory cortex; SMA, supplementary motor area; STPa, superior temporal polysensory area; TAL, talairach; TBP, total back pain; TNFi, tumor necrosis factor inhibitor; TPJ, temporoparietal junction.
commonly used in TNFi clinical trials. It has been observed that in some AS patients, there is a loss in effectiveness with long-term use of TNFi. Our data clearly show that after TNFi treatment, AS patients partially reversed the hyposensitivity in thermal and mechanical detection, compared with healthy subjects, on the foot (serving as a probe for the sensory processing at the low back region [L5/S1]). Along with this sensation improvement, the overall
quality of back pain in these patients tilted further away from neuropathy. These findings provide support to our previous speculation39 that the characteristic spine inflammation in AS might be potent enough to affect neighboring nerve roots using an “inflammatory radiculopathy” mechanism. This also suggests a minor role of mechanical contribution to the pathogenesis of AS pain. Moreover, we raise the possibility that peripheral mechanisms of TNFi in treating AS back pain might involve reducing spinal inflammation.2,32 4.2. Brain mechanisms of tumor necrosis factor inhibitors
Figure 4. Cortical areas corresponding to the TNFi treatment effects. A 2-stage approach was used to analyze changes in cortical thickness in the AS patients restricted to the predefined pain-related map (see Methods for details). Cortical thinning was constructed as the 1-sample group mean to identify cortical areas significantly altered by TNFi. Blue clusters indicate areas of cortical thinning after the TNFi treatment. The image-wide statistical threshold was set at corrected P , 0.05. AS, ankylosing spondylitis; IPS, inferior parietal sulcus; L/R, left and right hemispheres; M1, primary motor cortex; PMA, premotor area; SMA, supplementary motor area; TNFi, tumor necrosis factor inhibitor.
Brain imaging studies have shown that acute pain processing occurs across a distributed network of brain areas that are thought to include S1, S2, and the neighboring parietal operculum area for sensory discrimination; anterior and mid cingulate cortex (ACC/MCC), insula, and orbitofrontal areas for motivation-affect functions; the prefrontal and posterior parietal regions for cognitive appraisal; and the TPJ for attention and salience.24,33 However, the representation of chronic pain is not clear; although it is likely similar to acute pain, it could be dissimilar because of the particular nature of the chronic condition. Recent studies show that chronic pain induces a transition to a different cortical representation.1 Our findings of cortical areas associated with baseline AS pain reflect a transition in chronic pain conditions characterized by engaging more effective and cognitive processing, served by common pain processing areas (ie, S2, SMA, and posterior parietal cortex) and salience (TPJ) and less common
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Figure 5. Whole-brain cortical correlates for fatigue and TBP. Analysis similar to that shown in Figure 3, except extended to whole-brain. Blue clusters represented a negative correlation (ie, cortical thinning) between the change in cortical thickness and the percent relief in symptoms, including fatigue and TBP; the red cluster, however, showed a positive correlation (ie, cortical thickening). The imagewise statistical threshold was set at a corrected P , 0.05. IPS, inferior parietal lobe; L/R, left and right hemispheres; OFC, orbitofrontal cortex; S1/S2, primary/secondary somatosensory cortex; STPa, superior temporal polysensory area; TBP, total back pain.
pain areas (ie, fusiform gyrus and lingual cortex for visual emotional stimuli12,16,28). Moreover, the cortical areas that changed related to the relief in back pain and fatigue included areas associated with body sensation, awareness, and interoception, including S1, S2, and the insula. It is believed that cortical changes associated with chronic pain conditions and treatments are dependent on activity/ experience.21 Evidence shows that after effective treatment of pain cortical abnormalities, ie, in the cingulate cortex, the insula and prefrontal cortex could be reversed.15,22,27,29 We have previously shown that compared with matched healthy subjects, AS patients not on TNFi have cortical thinning in S1, SMA, cingulate, and insula.39 Surprisingly, our current data did not find that TNFi treatment reverses cortical thinning in these areas. In fact, the TNFi treatment was associated with cortical thickening of the TPJ, and further cortical thinning, compared with baseline and control values, in a different set of areas, classically attributed to cognitive and motor planning, multimode sensory integration, and visuomotor integration. The underlying causes of these unexpected findings are not clear and here we consider some possible factors. First, a detectable change in cortical thickness might simply require a longer treatment period. Second, cortical changes after TNFi might be because of a variety of both treatment-specific effects and nonspecific effects secondary to lifestyle changes associated with treatment, including more active social interactions, better mobility, and so on. Third, cortical thinning in cognitive and motor planning areas might reflect residual fatigue. In other chronic pain conditions such as osteoarthritis, effective treatments (ie, after joint replacement) normally result in good pain relief and minimal fatigue. However, as shown in this study, more than half of AS patients, after TNFi treatment, underwent a transition from a pain-dominant condition to a fatigue-dominant condition. In conclusion, we have demonstrated that TNFi has a greater effect on relieving back pain than fatigue in patients with AS. This suggests that residual fatigue could contribute to poor QoL. We
Figure 6. Total back pain and fatigue relief correlates with changes in cortical thickness after TNFi treatment. Data are shown for the change in cortical thickness (CT) with TNFi treatment (after TNFi minus before TNFi) correlated with the percent relief in TBP intensity and FSS scores in areas found to have a significant correlation (see Methods for details). All correlations are significant at P , 0.001: TBP and L OFC (r 5 0.798); TBP and R S2 (r 5 20.845); FSS and L insulin (r 5 20.908); FSS and L STPa (r 5 20.829); FSS and R S1/IPS (r 5 20.875); FSS and R STPa (S) (r 5 20.849); FSS and R STPa (S) (r 5 20.849). S1/S2, primary/secondary somatosensory cortex; STPa, superior temporal polysensory area; TBP, total back pain.
also showed that baseline pain, fatigue, disease severity, and positive emotion strength contribute to the effects of TNFi treatment on pain and fatigue relief. This is the first study to show that TNFi attenuates the neuropathic pain component of AS in addition to reversing sensory loss and improving lateral spinal mobility. This is also the first study to show specific changes in brain sensorimotor and salience gray matter regions related to AS pain and fatigue and TNFi treatment effects. Therefore, this study has important clinical implications in that it pinpoints the limited effect of TNFi for fatigue, demonstrates different brain mechanisms used by pain and fatigue relief, and raises the need to develop better fatigue coping strategies in AS patients on TNFi.
Conflict of interest statement The authors have no conflict of interest pertaining to this study.
Acknowledgements The authors acknowledge the assistance of from Adele Carty in clinical data retrieval, Ammepa Anton in patient recruitment, and Eugene Hlasny and Keith Ta in MRI acquisition. Informed consent was obtained for the study from the University Health Network.
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This study was supported by Canada Research Chair Program (CRC in Brain and Behaviour) and CIHR Operating Grant for KDD. Q. Wu was a recipient of the Pain Scientist Scholarship, University of Toronto Center for the Study of Pain, and the Postdoctoral Fellowship, Canadian Pain Society. Article history: Received 9 July 2014 Received in revised form 21 October 2014 Accepted 19 November 2014
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Tumor necrosis factor inhibitor therapy in ankylosing spondylitis: differential effects on pain and fatigue and brain correlates Qi Wua, Robert D. Inmanb,c,d, Karen D. Davisa,c,e,*
Abstract Ankylosing spondylitis is associated with back pain and fatigue and impacts mobility but can be treated with tumor necrosis factor inhibitors (TNFi). The differential effects of TNFi treatment on multiple symptoms and the brain is not well delineated. Thus, we conducted a 2-part study. In study 1, we conducted a retrospective chart review in 129 ankylosing spondylitis patients to assess TNFi effects on pain, fatigue, motor function, mobility, and quality of life (QoL). After at least 10 weeks of TNFi treatment, patients had clinically significant improvements (.30%) in pain (including neuropathic pain), most disease and QoL factors, and normalized sensory detection thresholds. However, residual fatigue (mean 5 5.3) was prominent. Although 60% of patients had significant relief of pain, only 22% of patients had significant relief of both pain and fatigue. Therefore, the preferential TNFi treatment effect on pain compared with fatigue could contribute to suboptimal effects on QoL. Part 2 was a prospective study in 14 patients to identify TNFi treatment effects on pain, fatigue, sensory and psychological factors, and brain cortical thickness based on 3T magnetic resonance imaging. Centrally, TNFi was associated with statistically significant cortical thinning of motor, premotor, and posterior parietal regions. Pain intensity reduction was associated with cortical thinning of the secondary somatosensory cortex, and pain unpleasantness reduction was associated with the cortical thinning of motor areas. In contrast, fatigue reduction correlated with cortical thinning of the insula, primary sensory cortex/inferior parietal sulcus, and superior temporal polysensory areas. This indicates that TNFi treatment produces changes in brain areas implicated in sensory, motor, affective, and cognitive functions. Keywords: Gray matter, Pain, Fatigue, Biologics, TNF
1. Introduction Ankylosing spondylitis (AS) is a debilitating rheumatic condition characterized by pain, fatigue, and reduced mobility that can severely affect quality of life (QoL) and work-related activity. Conventional symptom management, such as nonsteroidal antiinflammatory drugs and traditional disease-modifying antirheumatic oral drugs, has only modest efficacy. However, up to 60% of patients treated with tumor necrosis factor inhibitors (TNFi) have greatly improved serological parameters (ie, erythrocyte sedimentation rate, C-reactive protein) and radiological outcomes5,14,18,26,34 and improvement in pain and indicators of disease activity.17,20 Despite these positive outcomes of TNFi treatment for AS, the brain mechanisms underlying TNFi effects on pain and fatigue are not known. If fatigue correlates well with pain in patients with AS, then fatigue would be expected to be comparably improved with Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. a
Division of Brain, Imaging and Behaviour-Systems Neuroscience, Toronto Western Research Institute, Toronto, ON, Canada, b Division of Rheumatology, Toronto Western Hospital, Toronto, ON, Canada, c Institute of Medical Science, University of Toronto, Toronto, ON, Canada, Departments of d Medicine and, e Surgery, University of Toronto, Toronto, ON, Canada *Corresponding author. Address: Toronto Western Hospital, Room MP14-306, 399 Bathurst St, Toronto, ON M5T 2S8, Canada. Tel.: (416) 603-5662; fax: (416) 603-5745. E-mail address: [email protected] (K. D. Davis). PAIN 156 (2015) 297–304 © 2015 International Association for the Study of Pain http://dx.doi.org/10.1097/01.j.pain.0000460310.71572.16
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reduction of pain. However, this may not be the case. Previous studies report a considerable residual fatigue in patients with AS after treatment with TNFi37 regardless of the amount of pain relief.26 Our recent brain imaging investigation of the central mechanism of fatigue in AS indicates that pain and fatigue have differential effects on the brain; fatigue more strongly impacting motor and attentional networks40 than areas more classically implicated in pain perception.7 The aim of this study was to examine the differential effect of TNFi treatment on symptom relief in patients with AS with focus on pain and fatigue. Because there are distinct central mechanisms associated with pain and fatigue, we hypothesized that the relief of pain and fatigue by TNFi might have different trajectories. To test these hypotheses, we performed 2 studies: (1) a retrospective review of patients with AS to determine the efficacy of TNFi treatment on pain and fatigue and (2) a prospective brain imaging study in patients with AS to determine the brain plasticity associated with TNFi in general and specifically the brain effects related to the change in pain and fatigue after TNFi treatment.
2. Methods 2.1. Study participants Two study designs were used as follows: (1) a cross-sectional clinical assessment in 129 TNFi-treated patients with AS and (2) a prospective brain imaging/psychophysical assessment in 25 additional patients with AS and age/sex-matched controls. All patients were recruited from the Toronto Western Hospital AS www.painjournalonline.com
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Clinic where they received a standard treatment regimen of TNFi biologics for at least 10 weeks (a stable blood concentration is reached by this time point). In standard protocols and dosing as recommended by the ASAS/EULAR recommendations for the management of AS, TNFi biologics were given to patients.4 Sexand age-matched healthy subjects were recruited from the Toronto Western Research Institute community of staff and students, and they provided informed written consent to this study that was approved by the University Health Network Research Ethics Board. For study 1, clinical variables from 129 patients with AS were retrieved from the clinic’s AS database using the following inclusion criteria: (1) a diagnosis of AS according to the modified New York criteria,35 (2) current TNFi treatment, and (3) identifiable pretreatment and posttreatment time points and corresponding data. For study 2, an additional 25 patients with AS provided informed written consent for the psychophysics and magnetic resonance imaging (MRI) experiments and were recruited from the clinic using the following inclusion criteria: (1) fatigue severity scale (FSS) .3, (2) total back pain (TBP) .3 of 10 on a categorical rating scale from 0 to 10, (3) a stable dose of analgesics, and (4) not on biologics at the time of the study. Additional general inclusion criteria for all participants in the prospective study were age between 18 and 60 years, without severe psychiatric or neurological conditions (ie, depression, fibromyalgia) based on history and clinical interview, no history of diabetes, no major surgery within the past 2 years, and considered to be appropriate for brain MRI. Of the 25 patients with AS enrolled, 11 were excluded from the final longitudinal analysis for TNFi effects (8 of these 11 patients did not complete the TNFi treatment, 2 patients who received treatment were lost in follow-up, and 1 patient had MRI scans acquired with different parameters). 2.2. Clinical and psychophysical assessments and brain imaging For study 1, the AS database was used to identify demographic and clinical variables related to the efficacy of the TNFi characterized by disease-related variables such as TBP by a numerical rating scale, FSS, Bath AS disease activity, function, and metrology indices (bath ankylosing spondylitis disease activity index [BASDAI], bath ankylosing spondylitis function index [BASFI], and BASMI, respectively),36 and ASQoL. A clinically significant improvement threshold was set at “30% improvement” from baseline, which is a standard outcome measure in many chronic pain conditions including low back pain and osteoarthritis.9,23 For study 2, patients with AS completed questionnaires (including Pain Catastrophizing Scale31 [PCS], Affect Intensity Measure8 [AIM], painDETECT,11 and FSS19) and underwent psychophysic testing to determine sensory thresholds, and a 3T MRI scan, at 2 time points: before and 4 months after the start of TNFi treatment. Age- and sex-matched healthy controls also completed the PCS and AIM and underwent the psychophysical and MRI assessment. Patients with AS were asked to rate their average TBP they had over the past week on a categorical scale of 0 to 10. A modified, 9-item 10-point FSS was used to determine the severity of fatigue.19 The PCS (range 0-5231 and the 40-item 6-point scale AIM8 were used to assess the cognitive/affective functions as previously described.40 The painDETECT Questionnaire11 was used to determine the neuropathic component of AS pain. As described in our previous report,39 a standard psychophysics assessment was conducted to determine the mechanical and
thermal thresholds of the feet. Von Frey filaments (OptiHair2; Marstock Nervtest, Schriesheim, Germany) were used to determine mechanical thresholds (set of 12 monofilaments [contact surface, ;0.4 mm], bending forces from 0.25 to 512 mN). Subjects were instructed to close their eyes during the testing. Monofilaments were applied in ascending order, and subjects instructed to identify when they felt a sensation. Mechanical detection and pain thresholds in each subject were defined as the force of the finest filament to be detected and evoke pain, respectively. A computercontrolled Peltier device (TSA-II NeuroSensory Analyzer; Medoc Ltd, Ramat Yishai, Israel) with a 30 3 30-mm probe was used to deliver thermal stimuli on the skin to delineate thermal thresholds. From a baseline temperature of 32˚C, the probe temperature changed at a rate of 0.5˚C/s until the subject pressed a button to indicate the detection of sensation being assessed. The range of the delivered temperatures was between 0˚C and 50˚C. Three trials for cool and warm detection and 5 trials for cold pain and heat pain were run. Individual thresholds were calculated as the average of 3 trials for thermal detection and the last 4 of the 5 trials for thermal pain. 2.3. Magnetic resonance imaging data acquisition Study participants were scanned with a 3T GE MRI scanner equipped with an 8-channel phased-array head coil. T1weighted anatomical scans were acquired with the following parameters: 3D IR-FSPGR sequence; 180 axial slices, slice thickness 1 mm, matrix 256 3 256; 1 3 1 3 1 mm voxels; flip angle 5 15˚; TE 5 3 milliseconds; TI 5 450 milliseconds; and TR 5 7800 milliseconds. Brain MRI image processing and cortical thickness analyses (both cross-sectional and longitudinal) were done in Freesurfer 5.2, a standard commonly used software package (http:// freesurfer.net/). The imagewise significance was a corrected level of P , 0.05 (derived from 87 contiguous voxels for the region of interest [ROI] approach and 98 contiguous voxels for the wholebrain approach; 5000 iterations of Monte Carlo simulations). Sigmaplot (version 12; Systat Software, Inc, San Jose, CA) was used to deal with nonimaging data. The specific imaging methodological details are described below. All T1-weighted images were fed into a standard preprocessing pipeline including intensity normalization, skull stripping, separation of the hemispheres, and gray matter segmentation. For the longitudinal analysis, an additional “base step” was needed (after the above “cross” step), where an unbiased median image for each patient subject was established as the withinsubject template onto which images from the 2 time points were registered. Each time point, then, was processed “longitudinally” using the information from both the “cross” and “base” steps.25 Finally, a Gaussian smoothing kernel of 4-mm full-width half maximum was applied to the preprocessed images. Cortical thickness (for the cross-sectional analysis) or the difference in cortical thickness (for the prospective analysis) was extracted and modeled into voxelwise general linear models. T1-weighted images from a total of 22 AS patients at baseline were used to establish the whole-brain cortical correlates with either pain intensity ratings or pain unpleasantness ratings. Three of these patients were excluded from this analysis because of technical imaging issues and/or poor images. Cortical regions (Brodmann Areas) found to be associated with AS pain were identified with the cortical parcellations map implemented into FreeSurfer (Population-Average, Landmark- and Surface-based Brodmann Area Mask [PALS-B12]) (see http://freesurfer.net/), and used to create a ROI mask to guide subsequent longitudinal analysis in the 14 patients.
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2.4. Statistical analysis Clinical data from study 1 and nonimaging data from study 2 were analyzed with Statistical Package for the Social Sciences v16.0 (SPSS Inc, Chicago, IL). A Pearson normality test was run to determine whether data exhibited a normality distribution and whether parametric or nonparametric tests should be followed. Student t tests were used to compare baseline demographic variables and disease-related variables from study 1 and study 2. Depending on the data distribution, either paired t test or Wilcoxon signed-rank test was used to compare paired nonimaging data before and after the TNFi treatment, and either Pearson product–moment correlation or Spearman’s rank order correlation was used for bivariate correlation analyses. Forward stepwise selection was performed in multivariate general linear modeling. Correlation of cortical thickness values (extracted from FreeSurfer) with clinical variable was analyzed using SPSS, and correlation graphs were also generated using SPSS.
3. Results The patients in study 1 and study 2 did not differ in baseline demographic variables, such as age and sex composition, and the main disease-related variables, such as TBP and FSS (all P . 0.05; Table 1).
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DOMJAN (lateral spinal mobility to the left), and ASQoL (all P , 0.001; paired t test; Table 1 and Fig. 1). The improvements in pain and disease activity, function, and metrology index were a .30% reduction compared with the baseline. However, the improvement in fatigue was only 19.7% of baseline values (Fig. 1). The % reductions in TBP and FSS were significantly correlated % (r 5 0.422, P , 0.001; Pearson product–moment correlation test; Fig. 1). Although 60% of patients had .30% pain reduction, only 35% of patients had .30% fatigue reduction and only 20% of the patients had .30% improvement in both pain and fatigue. After treatment, AS patients still suffered a considerable amount of fatigue (residual FSS 5 5.3 6 2.7). We also found that 57% of AS patients had a residual FSS score .5, whereas only 24% of them had a residual FSS score ,3, which was slightly improved compared with the baseline where 72% of patients had an FSS score .5 and 11% with an FSS score ,3. Both TBP and FSS significantly correlated with ASQoL at both time points (all P , 0.001, Spearman’s rank order correlation). After the treatment, the residual fatigue became the main source of the posttreatment ASQoL accounting for 60.4% of variance (TBP for an addition of 7.1%; stepwise multiple regression). This contrasted the baseline scenario, where TBP was the main ASQoL determinant accountable for 35.2% of variance and FSS as the secondary adding another 16.9% of variance.
3.1. Efficacy of tumor necrosis factor inhibitors in AS patients: a cross-sectional survey
3.2. Effects of tumor necrosis factor inhibitors on peripheral sensory processing in ankylosing spondylitis patients: a longitudinal study
The average duration of TNFi treatment in study 1 was 59.3 weeks (range, 10-256 weeks). The TNFi significantly improved most major AS-related variables, including TBP, FSS, BASDAI, BASFI, left
To understand how TNFi treatment changes the quality and potential neuropathic contribution to back pain, we administrated the painDETECT questionnaire to the patients in study 2. After TNFi
Table 1
Ankylosing spondylitis patient demographics and sensory thresholds. Study 1 (N 5 129) Before Age, y Sex TBP FSS BASDAI BASFI QoL DOMJAN L DOMJAN R PCS AIM painDETECT MD L, mN MD R, mN MP L, mN MP R, mN CD L, ˚C CD R, ˚C CP L, ˚C CP R, ˚C WD L, ˚C WD R, ˚C HP L, ˚C HP R, ˚C
Study 2 (N 5 14) After
43.6 6 11.4 34 female/95 male 6.7 6 2.5 6.6 6 2.5 6.4 6 2.0 5.6 6 2.4 11.7 6 4.9 11.9 6 6.1 13.4 6 6.4 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA
3.7 6 2.8* 5.3 6 2.6* 3.6 6 2.2* 3.5 6 2.7* 7.3 6 5.9* 13.2 6 6.1* 13.5 6 6.2 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA
Controls
Before
37.2 6 10.2 NA NA NA NA NA NA NA 13.7 6 10.6 3.6 6 0.4 NA 1.6 6 1.4 1.1 6 0.6 95.7 6 95.6 82.1 6 86.6 29.3 6 1.8 29.6 6 1.6 15.1 6 10.3 15.7 6 10.1 36.5 6 3.1 35.3 6 1.9 44.9 6 2.7 44.2 6 3.7
After 37.6 6 11.9 3 female/11 male
6.0 6 1.7 6.5 6 2.8 NA NA NA NA NA 23.7 6 12.9 3.9 6 0.6 12.9 6 7.4 2.8 6 2.6 2.5 6 2.6 78.3 6 142.8 83.4 6 138.8 27.6 6 3.5 28.2 6 1.9 14.2 6 8.7 15.5 6 8.4 37.9 6 4.0 36.8 6 2.2 45.7 6 2.5 44.9 6 10
3.8 6 2.5† 5.9 6 3.2 NA NA NA NA NA 18.5 6 12.9† 3.9 6 0.5 8.9 6 6.0 2.4 6 2.7 1.5 6 1.3† 79.1 6 131.1 80.6 6 139.5 27.7 6 2.4 28.1 6 2.4 15.0 6 9.1 14.2 6 9.8 36.9 6 3.2† 37.2 6 3.3 46.1 6 2.9 45.3 6 3.8
Values are represented as mean 6 SD. No other significant comparisons were found in any parameters in studies 1 and 2. There was no difference between study 1 and 2 in age, sex composition, baseline TBP or baseline FSS. * P , 0.001 (paired t test) compared with the baseline in study 1. † P , 0.05 (paired t test) compared with the baseline in study 2. AIM, Affect Intensity Measure; BASDAI, bath ankylosing spondylitis disease activity index; BASFI, bath ankylosing spondylitis function index; CD, cold detection threshold; CP, cold pain threshold; DOMJAN, DOMJAN score of lateral spinal mobility; FSS, fatigue severity scale; HP, heat pain threshold; L/R, left/right foot; MD, mechanical detection threshold; MP, mechanical pain threshold; NA, not available; PCS, Pain Catastrophizing Scale; QoL, quality of life; TBP, total back pain; WD, warm detection threshold.
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Figure 2. Effect of TNFi on painDETECT scores in AS patients (study 2). Individual painDETECT scores were obtained before and after treatment with a TNFi. The dotted line depicts the painDETECT level of 12, indicating a possible neuropathic component. Fourteen patients in study 2 were included in the analysis. AS, ankylosing spondylitis; TNFi, tumor necrosis factor inhibitor.
3.3. Baseline features associated with pain and fatigue relief Figure 1. Efficacy of TNFi in pain and fatigue relief in AS patients (study 1). Top left panel: TNFi significantly reduced the TBP (P , 0.001, paired t test), which was .30% reduction of the baseline and was therefore of clinical significance as well. Top right panel: TNFi statistically significantly reduced the FSS (P , 0.001, paired t test); however, this was not of clinical significance as the degree of improvement was ,30% reduction of the baseline. Bottom panel: the percentage improvements in TBP and FSS were significantly correlated; only a small portion of patients (plots of the top right corner) had clinical improvements in both TBP and FSS (.30% of reduction of the baseline, indicated by dotted lines). AS, ankylosing spondylitis; FSS, fatigue severity scale; TBP, total back pain; TNFi, tumor necrosis factor inhibitor.
treatment, the group painDETECT scores were significantly reduced (P , 0.05, paired t test, Table 1). Reduced scores occurred for patients who had baseline scores above and below the level of 12 that indicates a likelihood of neuropathic pain component. Specifically, of the 7 patients with baseline painDETECT scores above 12, 5 had reduced scores after TNFi treatment (3 below 12). Of the 7 patients with baseline painDETECT scores below 12, 5 had decreased scores after treatment (Fig. 2). The effect of treatment on pain, FSS, and PCS scores for each patient after treatment is provided in Table 2. To investigate how the treatment affects sensory thresholds, we determined psychophysical thresholds and found that, compared with the baseline values, the mechanical detection threshold on the right foot was significantly lower after the treatment (P , 0.05, Wilcoxon signed-rank test; Table 1) and the warm detection threshold on the left foot was significantly lower after the treatment (P , 0.05, paired t test; Table 1). No other sensory thresholds were altered by the treatment (Table 1).
To determine whether any baseline clinical variables (TBP, FSS, BASDAI, BASFI, or ASQoL) could account for the efficacy of the TNFi treatment (in terms of percent relief in TBP or fatigue), we included all these variables in multivariate models using the forward stepwise approach. For the patients in study 1, the percent relief in TBP was related to the baseline TBP (r 5 0.451, P , 0.05) and BASDAI (r 5 0.497, P , 0.05), and the percent relief in fatigue was related to the baseline FSS (r 5 0.296, P , 0.01). Furthermore, we asked whether any baseline cognitive and sensory variables were associated with the percent reduction in pain or fatigue using data from study 2. We found that the percent relief in back pain intensity was correlated with the baseline AIM (intensity of positive emotion, r 5 0.655, P , 0.01; Pearson product–moment correlation test), the percent relief in FSS was correlated with the baseline mechanical detection threshold of the left foot (r 5 20.543, P , 0.05; Pearson product–moment correlation test), and the residual fatigue was correlated with the mechanical detection thresholds of both feet (left, r 5 0.633, P , 0.05; right, r 5 0.616, P , 0.05; Pearson product–moment correlation test). 3.4. Ankylosing spondylitis pain–related cortical thickness abnormalities and the effects of tumor necrosis factor inhibitors In 22 AS patients not yet treated with TNFi, we found that TBP was positively correlated with cortical thickness of the temporoparietal junction (TPJ) and negatively correlated with cortical thickness of the left primary and supplementary motor area (M1 and SMA), anterior mid-cingulate cortex and lingual gyrus, the
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Table 2
Self-reported pain-related ratings in patients with AS in study 2. ID/Age/Sex
Interval, wk*
Before TNFi 1/22/M 2/50/M 3/36/F 4/50/M 5/60/M 6/37/M 7/34/M 8/31/M 9/30/M 10/22/F 11/37/M 12/27/M 13/55/M 14/26/F After TNFi 1/22/M 2/50/M 3/36/F 4/50/M 5/60/M 6/37/M 7/34/M 8/31/M 9/30/M 10/22/F 11/37/M 12/27/M 13/55/M 14/26/F
17 20 47 18 19 15 14 34 33 30 35 19 19 18
PCS
AIM
TBP
painDETECT
FSS
47 28 21 44 1 5 36 25 12 23 24 26 20 20
4.7 3.7 4 4.8 3.9 3.1 4.7 3.9 4.1 4.6 3.3 3 3 4.1
8 7 6 6 7 4 7 5 7 8 6 3 7 3
24 17 4 11 21 7 13 11 14 25 3 18 3 9
10 4.1 8.6 9.7 6.9 1.7 10 5.3 5.2 8.1 4.4 8.7 1.8 6.6
38 16 21 47 2 7 14 28 26 21 16 11 8 4
5.1 4.1 4.2 4.2 4.1 3.2 4.6 3.3 4.5 4.6 3.2 3.5 3.4 3.8
4 6 8 5 7 1 1 1 6 2 6 3 2 1
11 10 1 8 21 4 5 14 13 18 7 5 1 6
9.4 8.6 8.6 9.6 6.8 0.7 2 8.9 7.7 7 4.4 5.7 1.2 2.9
* Represents the interval between the initiation of TNFi treatment and the follow-up MRI scan. AIM, Affect Intensity Measure; AS, ankylosing spondylitis; FSS, fatigue severity scale; MRI, magnetic resonance imaging; PCS, Pain Catastrophizing Scale; TBP, total back pain; TNFi, tumor necrosis factor inhibitor.
right secondary sensory cortex (S2) and fusiform, and bilateral inferior parietal lobe (Fig. 3, Table 3). These areas were used to generate an ROI brain mask to represent AS back pain. For the patients who were scanned after TNFi treatment, we found cortical thinning in 3 regions within the ROI mask: the left M1/ SMA, the left inferior parietal sulcus, and the right premotor area (Table 3 and Fig. 4). 3.5. Cortical correlates of the tumor necrosis factor inhibitors–induced pain and fatigue relief We next correlated for each patient, the percent TBP relief with changes in cortical thickness at the whole-brain level. This analysis revealed that the percent reduction TBP was correlated with cortical thinning of the right S2 and with the cortical thickening of the left orbitofrontal cortex, whereas the percent fatigue relief was correlated with cortical thinning of the left insula, the right primary sensory cortex/inferior parietal sulcus border area, and bilateral superior temporal polysensory areas (Figs. 5 and 6, Table 3).
4. Discussion The present data demonstrate that TNFi has a greater effect on relieving back pain than fatigue; with only a small portion of AS patients reporting improvements in both pain and fatigue. This finding highlights an important limitation of TNFi for treatment of AS given that the residual fatigue can be a major contributor of
Figure 3. Cortical areas in AS related to baseline TBP. Whole-brain analysis of cortical areas associated with TBP at the baseline AS patients was overlaid onto the average brain. Blue clusters, negative correlations of cortical thickness with TBP; the red cluster, a positive correlation. All involved areas were built as the ROI mask for further longitudinal analyses. aMCC, anterior mid-cingulate cortex; IPL, inferior parietal lobule (containing the temporoparietal junction); Lingual, lingual gyrus; L/R, left and right hemispheres; M1, primary motor cortex; SMA, supplementary motor area; S2, secondary somatosensory cortex; TBP, total back pain.
poor QoL. The data also suggest that baseline factors, such as pain, fatigue, disease severity, and positive emotion strength, may contribute to the effects of pain and fatigue relief. Furthermore, we found other effects of TNFi including attenuated neuropathic pain, reversal of sensory loss and improved lateral spinal mobility, and altered cortical thickness. 4.1. Clinical effects of tumor necrosis factor inhibitors Our retrospective chart review confirms previous observations about the effectiveness of TNFi in a wide range of disease-related variables in AS patients,3,5,13,14,18,34 including BASDAI, BASFI, TBP and QoL, although it should be noted that a limitation of this study was that it was not formally placebo controlled. It has been shown that pain and fatigue, together with sleep disturbance and stiffness, are the QoL concerns in AS patients.38 Therefore, we focused on the association of pain relief with the impact of TNFi on fatigue and found that only a modest proportion (22%) of patients reported significant improvement in both these key areas. Although differences in sensitivity across pain and fatigue scales may explain why the effect of TNFi was clinically significant for pain but not for fatigue, these findings are somewhat at odds with previous findings. Some studies report significant and satisfactory fatigue relief by TNFi.3,6,13 Our earlier clinical trial in pilot subjects showed that significant relief of fatigue occurs rapidly after 6 weeks of TNFi treatment,30 although this significance became borderline (P 5 0.0299) after 14 weeks on TNFi. However, other studies report poor responsiveness of fatigue to TNFi.26,37 In our current survey of patients on long-term TNFi (average 59 weeks), patients only had a modest 20% relief in fatigue. Additional analysis showed that 57% of patients were still fatigued (FSS . 5) and that the residual fatigue became the primary QoL factor after the treatment. Several factors might account for this discrepancy regarding TNFi and fatigue. First, most studies that report good responsiveness of fatigue to TNFi use a single-item scale for fatigue measure, which might not be as accurate as the multi-item FSS used in this study.10 Second, the duration of TNFi treatment in our study was much longer than
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Table 3
Cortical areas associated with TNFi, TBP, and fatigue in patients with AS. BA
Region Whole-brain analysis: correlation with TBP before TNFi 4/6 40 39 32 18 20 37 39 41/43 ROI analysis: cortical thickness changes after TNFi* 4/6 7/19 6 Whole-brain analysis: percent TBP relief after TNFi 11 43 Whole-brain analysis: percent fatigue relief after TNFi 22/39 2/7 22 22
T value
Size (voxels)
50 35 31 35 2 212 3 41 19
25.123 3.383 23.717 22.939 23.198 23.631 23.555 24.214 23.588
113 102 107 105 142 163 99 118 143
210 270 24
55 29 47
24.526 23.257 23.065
108 93 93
224 54
27 213
212 19
3.218 23.687
99 103
232 250 31 63 57
221 249 239 226 228
10 6 47 3 29
24.735 23.714 24.079 23.809 25.167
145 141 144 119 127
Peak (TAL, mm) x
y
z
SMA/M1 IPL/TPJ IPL/TPJ aMCC Lingual gyrus Fusiform Fusiform IPL S2
224 249 240 211 29 37 50 39 45
210 256 258 21 272 232 255 264 220
M1/SMA IPS PMA
217 223 22
OFC S2
Insula STPa S1/IPS STPa STPa
Negative x coordinates indicate left brain. * Corresponding cortical thickness (mean, mm) in patients at both time points and in matched healthy subjects are provided as follows: the left BA4/6 cluster (before, 2.5; post, 2.3; control, 2.6); the left BA7/19 cluster (before, 2.1; post, 2.0; control, 2.2); and the right BA6 cluster (before, 2.5; post, 2.3; control, 2.5). aMCC, anterior mid-cingulate cortex; AS, ankylosing spondylitis; BA, Brodmann area; IPL, inferior parietal lobe (part of TPJ); IPS, inferior parietal sulcus; M1, primary motor cortex; OFC, orbitofrontal cortex; PMA, premotor area; ROI, region of interest; S1/S2, primary/secondary somatosensory cortex; SMA, supplementary motor area; STPa, superior temporal polysensory area; TAL, talairach; TBP, total back pain; TNFi, tumor necrosis factor inhibitor; TPJ, temporoparietal junction.
commonly used in TNFi clinical trials. It has been observed that in some AS patients, there is a loss in effectiveness with long-term use of TNFi. Our data clearly show that after TNFi treatment, AS patients partially reversed the hyposensitivity in thermal and mechanical detection, compared with healthy subjects, on the foot (serving as a probe for the sensory processing at the low back region [L5/S1]). Along with this sensation improvement, the overall
quality of back pain in these patients tilted further away from neuropathy. These findings provide support to our previous speculation39 that the characteristic spine inflammation in AS might be potent enough to affect neighboring nerve roots using an “inflammatory radiculopathy” mechanism. This also suggests a minor role of mechanical contribution to the pathogenesis of AS pain. Moreover, we raise the possibility that peripheral mechanisms of TNFi in treating AS back pain might involve reducing spinal inflammation.2,32 4.2. Brain mechanisms of tumor necrosis factor inhibitors
Figure 4. Cortical areas corresponding to the TNFi treatment effects. A 2-stage approach was used to analyze changes in cortical thickness in the AS patients restricted to the predefined pain-related map (see Methods for details). Cortical thinning was constructed as the 1-sample group mean to identify cortical areas significantly altered by TNFi. Blue clusters indicate areas of cortical thinning after the TNFi treatment. The image-wide statistical threshold was set at corrected P , 0.05. AS, ankylosing spondylitis; IPS, inferior parietal sulcus; L/R, left and right hemispheres; M1, primary motor cortex; PMA, premotor area; SMA, supplementary motor area; TNFi, tumor necrosis factor inhibitor.
Brain imaging studies have shown that acute pain processing occurs across a distributed network of brain areas that are thought to include S1, S2, and the neighboring parietal operculum area for sensory discrimination; anterior and mid cingulate cortex (ACC/MCC), insula, and orbitofrontal areas for motivation-affect functions; the prefrontal and posterior parietal regions for cognitive appraisal; and the TPJ for attention and salience.24,33 However, the representation of chronic pain is not clear; although it is likely similar to acute pain, it could be dissimilar because of the particular nature of the chronic condition. Recent studies show that chronic pain induces a transition to a different cortical representation.1 Our findings of cortical areas associated with baseline AS pain reflect a transition in chronic pain conditions characterized by engaging more effective and cognitive processing, served by common pain processing areas (ie, S2, SMA, and posterior parietal cortex) and salience (TPJ) and less common
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Figure 5. Whole-brain cortical correlates for fatigue and TBP. Analysis similar to that shown in Figure 3, except extended to whole-brain. Blue clusters represented a negative correlation (ie, cortical thinning) between the change in cortical thickness and the percent relief in symptoms, including fatigue and TBP; the red cluster, however, showed a positive correlation (ie, cortical thickening). The imagewise statistical threshold was set at a corrected P , 0.05. IPS, inferior parietal lobe; L/R, left and right hemispheres; OFC, orbitofrontal cortex; S1/S2, primary/secondary somatosensory cortex; STPa, superior temporal polysensory area; TBP, total back pain.
pain areas (ie, fusiform gyrus and lingual cortex for visual emotional stimuli12,16,28). Moreover, the cortical areas that changed related to the relief in back pain and fatigue included areas associated with body sensation, awareness, and interoception, including S1, S2, and the insula. It is believed that cortical changes associated with chronic pain conditions and treatments are dependent on activity/ experience.21 Evidence shows that after effective treatment of pain cortical abnormalities, ie, in the cingulate cortex, the insula and prefrontal cortex could be reversed.15,22,27,29 We have previously shown that compared with matched healthy subjects, AS patients not on TNFi have cortical thinning in S1, SMA, cingulate, and insula.39 Surprisingly, our current data did not find that TNFi treatment reverses cortical thinning in these areas. In fact, the TNFi treatment was associated with cortical thickening of the TPJ, and further cortical thinning, compared with baseline and control values, in a different set of areas, classically attributed to cognitive and motor planning, multimode sensory integration, and visuomotor integration. The underlying causes of these unexpected findings are not clear and here we consider some possible factors. First, a detectable change in cortical thickness might simply require a longer treatment period. Second, cortical changes after TNFi might be because of a variety of both treatment-specific effects and nonspecific effects secondary to lifestyle changes associated with treatment, including more active social interactions, better mobility, and so on. Third, cortical thinning in cognitive and motor planning areas might reflect residual fatigue. In other chronic pain conditions such as osteoarthritis, effective treatments (ie, after joint replacement) normally result in good pain relief and minimal fatigue. However, as shown in this study, more than half of AS patients, after TNFi treatment, underwent a transition from a pain-dominant condition to a fatigue-dominant condition. In conclusion, we have demonstrated that TNFi has a greater effect on relieving back pain than fatigue in patients with AS. This suggests that residual fatigue could contribute to poor QoL. We
Figure 6. Total back pain and fatigue relief correlates with changes in cortical thickness after TNFi treatment. Data are shown for the change in cortical thickness (CT) with TNFi treatment (after TNFi minus before TNFi) correlated with the percent relief in TBP intensity and FSS scores in areas found to have a significant correlation (see Methods for details). All correlations are significant at P , 0.001: TBP and L OFC (r 5 0.798); TBP and R S2 (r 5 20.845); FSS and L insulin (r 5 20.908); FSS and L STPa (r 5 20.829); FSS and R S1/IPS (r 5 20.875); FSS and R STPa (S) (r 5 20.849); FSS and R STPa (S) (r 5 20.849). S1/S2, primary/secondary somatosensory cortex; STPa, superior temporal polysensory area; TBP, total back pain.
also showed that baseline pain, fatigue, disease severity, and positive emotion strength contribute to the effects of TNFi treatment on pain and fatigue relief. This is the first study to show that TNFi attenuates the neuropathic pain component of AS in addition to reversing sensory loss and improving lateral spinal mobility. This is also the first study to show specific changes in brain sensorimotor and salience gray matter regions related to AS pain and fatigue and TNFi treatment effects. Therefore, this study has important clinical implications in that it pinpoints the limited effect of TNFi for fatigue, demonstrates different brain mechanisms used by pain and fatigue relief, and raises the need to develop better fatigue coping strategies in AS patients on TNFi.
Conflict of interest statement The authors have no conflict of interest pertaining to this study.
Acknowledgements The authors acknowledge the assistance of from Adele Carty in clinical data retrieval, Ammepa Anton in patient recruitment, and Eugene Hlasny and Keith Ta in MRI acquisition. Informed consent was obtained for the study from the University Health Network.
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This study was supported by Canada Research Chair Program (CRC in Brain and Behaviour) and CIHR Operating Grant for KDD. Q. Wu was a recipient of the Pain Scientist Scholarship, University of Toronto Center for the Study of Pain, and the Postdoctoral Fellowship, Canadian Pain Society. Article history: Received 9 July 2014 Received in revised form 21 October 2014 Accepted 19 November 2014
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