ORIGINAL RESEARCH

Assessment of Neuropathic Pain in AnkylosingSpondylitis: Prevalence and Characteristics

Ling Zhou . Ting Li . Xin Wu . Hongjuan Lu . Li Lin . Lingying Ye . Jian Yin . Juan Zhao .

Xiuwen Wang . Jianye Bian . Huji Xu

Received: June 30, 2021 /Accepted: August 13, 2021 / Published online: September 4, 2021� The Author(s) 2021

ABSTRACT

Introduction: Pain in ankylosing spondylitis iscurrently considered an inflammatory pain (IP).However, it was found that some patients stillhad the sensation of pain even withoutinflammation. Our study was to investigate theprevalence and characteristics of neuropathicpain (NeP) in Chinese Han ankylosingspondylitis (AS) patients.Methods: The study consisted of three parts.Firstly, we assessed the prevalence and clinicaldata of NeP in 182 AS patients. Secondly, weevaluated pain improvement after etanercepttherapy in 63 patients. Finally, serum neuro-transmitters were measured for 20 AS patientsand ten healthy controls (HC).

Results: Out of 182 AS patients, our studyshowed that 14 patients (7.70%) had likely NePand 55 (30.21%) had uncertain NeP. There weresignificant differences among the three groupswith respect to nocturnal pain (NP), peripheralpain (PP), total back pain (TBP), BASDAI,ASDAS-CRP, HAD-A, HAD-D, and BASDAI-fatigue except fort CRP concentrations. Principalcomponent analysis (PCA) of AS pain revealedthat the weight of NeP was greater than PP inthe first principal component (0.703 vs. 0.639).Structural equation modeling (SEM) revealedthat NeP altered disease activity (b = 0.62,P\ 0.001), which influenced psychologicalstatus (b = 0.42, P\ 0.001). Of 63 patients whoused etanercept for 3 months, significantimprovement was found in NP, TBP, and PP (allP\ 0.0001) but not in PDQ (10.60 ± 6.85 vs.9.98 ± 6.40, P = 0.0671). Serum nore-pinephrine concentrations in patients withPDQ[19 were higher than those in patientswith PDQ B 19 and HC.Conclusions: We conclude that NeP con-tributes to pain in AS patients.

Keywords: Ankylosing spondylitis; Neuropathicpain; Neurotransmitters

Ling Zhou and Ting Li contributed equally to this work.

L. Zhou � T. Li � X. Wu � H. Lu � L. Lin � L. Ye �J. Yin � J. Zhao � X. Wang � J. Bian � H. Xu (&)Department of Rheumatology and Immunology,Shanghai Changzheng Hospital, Naval MedicalUniversity, 415 Fengyang Road, Shanghai 200003,Chinae-mail: xuhuji@smmu.edu.cn

H. XuPeking-Tsinghua Center for Life Sciences, TsinghuaUniversity, Beijing 100084, China

H. XuSchool of Clinical Medicine, Tsinghua University,Beijing 100084, China

Pain Ther (2021) 10:1467–1479

https://doi.org/10.1007/s40122-021-00310-8

Key Summary Points

Why carry out this study?

Pain in ankylosing spondylitis (AS) iscurrently considered an inflammatorypain (IP). However, it was found that somepatients still had the sensation of paineven without inflammation.

Our study was to evaluate the prevalenceand characteristics of neuropathic pain(NeP) in AS patients, and to investigatethe difference between NeP and IP,especially in the outcome of anti-TNFtreatment and the serum concentration ofneurotransmitters.

What was learned from the study?

Our study showed that 37.91% of ASpatients had likely or uncertain NeP.Principal component analysis (PCA) of ASpain revealed that the weight of NeP wasgreater than peripheral pain (PP) in thefirst principal component (0.703 vs.0.639). pain-DETECT Questionnaire(PDQ) was not significantly improvedafter etanercept treatment (10.60 ± 6.85vs. 9.98 ± 6.40, P = 0.0671). Serumnorepinephrine concentrations inpatients with positive PDQ were higherthan those in patients with negative PDQand healthy controls (HC).

NeP is an important component of ASpain. TNF inhibitors do not appear to beas effective as expected in improving AS-associated NeP. Our result suggested thatinterference with neurotransmitteractivity may be a promising newtreatment for AS-associated NeP.

INTRODUCTION

Ankylosing spondylitis (AS) is an autoinflam-matory disease with a largely unknown

etiology. It primarily involves the axial skeletonand is characterized by sacroiliac arthritis andenthesitis with pain, stiffness, and joint defor-mity [1]. The pain in AS patients is currentlyconsidered as an inflammatory pain (IP). How-ever, the pain in AS patients is not always cor-related with the inflammatory indexes of thedisease, such as C-reactive protein (CRP) or theerythrocyte sedimentation rate (ESR) [2]. Bio-logics are the most effective treatment for AS atpresent. It was reported that the serologicalparameters and radiological outcomes wereimproved in approximately 60% of AS patientswho received tumor necrosis factor (TNF) inhi-bitors [3]. However, there is a weak correlationbetween change of inflammation (CRP lever)and back pain in patients with AS after treat-ment TNF inhibitors [4], while the pain lingerseven in the absence of inflammation afteradministration of the biologics in clinical prac-tice. In 2017, Bidad et al. found that AS-associ-ated pain is not merely attributed toinflammatory pain (IP) but also involves neu-ropathic pain (NeP) [2].

To date, no large-scale clinical trials havebeen performed to distinguish IP from NeP.Given the large population of AS patients inChina and the heavy economic burden onsociety and individuals, it is extremely impor-tant to find an accurate and practical tool fordifferentiating between IP and NeP. The pain-DETECT Questionnaire (PDQ) has proven to bean easily accessible and reliable tool for NePscreening. The PDQ consists of nine simple self-assessment questions suitable for patient self-scoring and large-scale epidemiological investi-gation [5].

Our study was to investigate the prevalenceand characteristics of NeP in Chinese Han ASpatients. We hypothesized that NeP contributedto AS pain with non-inflammatorycharacteristics.

METHODS

1. Part one: In the present study, we selected182 patients with a diagnosis of AS in hos-pitalization or clinic in our Department ofRheumatology & Immunology from

1468 Pain Ther (2021) 10:1467–1479

January 2019 to October 2019. The patientswho aged C 18 and diagnosed AS followingthe 1984 modified New York Criteria [6]were permitted to be enrolled. The patientswith fibromyalgia were excluded at enroll-ment. The patients with fibromyalgia, witha previous diagnosis or under treatment forNeP, previous diagnosis of psychiatric orneurologic conditions, or increased risk todevelop neuropathic disorders such asuncontrolled diabetes or neuroendocrine orneurovascular disorders were excluded.Patients using neuropsychiatric drugs orbiologics were also excluded (shown inFig. 1). The general data collected for thesepatients included age, gender, duration,medication, etc. The Bath AnkylosingSpondylitis Disease Activity Index (BASDAI)[7], the CRP-based Ankylosing SpondylitisDisease Activity Score (ASDAS-CRP) [8], andthe BASDAI-Fatigue score were used [9]. NePwas assessed by PDQ [5]. Anxiety anddepression levels were determined by usingthe Hospital Anxiety and Depression Scale(HAD) [10]. Nocturnal pain (NP) and totalback pain (TBP) were assessed by a visual

analogue scale (VAS). Peripheral pain (PP)was assessed by Q3 of BASDAI.

2. Part two: 105 out of 182 patients startedbiologics treatment, including etanercept(n = 63), infliximab (n = 10), adalimumab(n = 28) and golimumab (n = 4), based on ajoint decision by the patient and therheumatologist [11]. This part of the studyincluded 63 AS patients (31 with PDQ[12and 32 with PDQ B 12) who received asubcutaneous injection of 25 mg etanercept(Enbrel), twice a week for 12 weeks and hadno other concomitant medicines. Beforeadministration, all patients underwentstrict screening tests for tuberculosis, hep-atitis, and tumors. The main clinical param-eters included age, gender, ASDAS-CRP,BASDAI-Fatigue, PDQ, and HAD, whichwere recorded before and after medicationadministration.

3. Part three: 6 AS patients with PDQ[ 19 and14 age- and gender-matched patients withPDQ B 19 after Enbrel treatment wereincluded in this part of study, and 10 age-and gender-matched healthy individualswere used as the controls. Serum

Fig. 1 Flow chart of inclusion and exclusion criteria

Pain Ther (2021) 10:1467–1479 1469

neurotransmitter concentrations, includingnorepinephrine (NE), 5-hydroxytryptamine(5HT), glycine (Gly), glutamic acid (Glu), c-aminobutyric acid (GABA), 5-hydroxyin-doleacetic acid (5HIAA), kynurenine(KYN), and tryptophan (TRP), were mea-sured. Differences in the concentrations ofthese neurotransmitters were comparedamong the three groups. All blood sampleswere sent to Anpel Laboratory Technologies(Shanghai, China) for testing.

4. PDQ calculation: The PDQ includes ninesimple self-assessment questions with noneed for physical examination and there-fore is suitable for self-assessment and large-scale epidemiological investigation [5]. Ofthe nine questions, seven are weightedsensory items, which are scored by using a0–5 scoring system to indicate severity, andthe other two were related to radiating painand the mode of pain onset. Cut-offs wereapplied for analysis of the PD-Q as previ-ously described. A total score of nine itemsB 12 indicates a Nep is not likely, whereas ascore C 19 indicates that a Nep is likely.Between PD-Q scores of 12 and 19, Nep canbe present, but is uncertain.HAD score: Anxiety and depression wereevaluated by using the HAD, in which ascore of 0–7 indicates no anxiety or depres-sion, 8–10 for possible anxiety or depres-sion, and 11–21 for a high probability ofboth.The study was conducted according to theHelsinki Declaration and approved by thelocal ethics committee (ID: 2017SL046). Allthe patients gave their written informedconsent before inclusion in the study.

5. Statistical analyses: Statistical analysis wereconducted with SPSS software (ver. 16.0).The data that has a normal distribution arepresented as the mean ± SD. Continuousvariables with a normal distribution wereevaluated using a two-sample t test. Analy-sis of variance (ANOVA) was employed tolook for multigroup differences, and unor-dered categorical variables were assessed bythe Chi-squared test. Principal componentanalysis (PCA) was performed by dimensionreduction processing with SPSS statistical

software. Structural equation modeling(SEM) was analyzed using Amos ver.23.0.0, and any possible relationshipsbetween latent variables were evaluatedusing SEM.

RESULTS

1. General clinical information of AS patients(1) Of the 182 AS patients who participated

in the first phase of the study, a total of 14patients (7.7%) had PDQ scores of C 19 (prob-able Nep), 55 patients (30.21%) had PDQ scoresrated between 12 and 19 (uncertainty of Nep)and 113 patients (62.08%) had PDQ scores B 12(unlikely Nep). Cronbach’s a coefficient of thePDQ was analyzed to determine the internalconsistency of the PDQ in assessing NeP in ASpatients. The results showed that the Cron-bach’s a coefficient of the PDQ in AS patientswas 0.92, suggesting that the PDQ had a rela-tively high internal consistency and reliability.

(2) There were significant differences in NP(mean ± standard deviation [SD]: 2.25 ± 2.85vs. 5.34 ± 4.55 vs. 5.87 ± 3.02, P\ 0.0001),TBP (mean ± SD: 2.23 ± 2.62 vs. 5.54 ± 4.92vs. 5.85 ± 2.48, P\0.0001), and PP (mean ±

SD: 1.25 ± 1.79 vs. 2.44 ± 2.40 vs. 4.54 ± 2.54,P\ 0.0001) among the three groups (PDQB 12, 12\ PDQ\ 19 and PDQ C 19). Therewere significant differences in BASDAI, ASDAS,and psychological status, including anxiety,depression, and fatigue, except for CRP(mean ± SD: 12.75 ± 18.12 vs. 14.41 ± 11.79vs. 16.77 ± 11.36, P = 0.6057) (Table 1).

2. PCA: Determined by PCA, the first princi-pal component accounted for 62.7% of thepopulation variance. The first principal com-ponent was calculated as follows:

F1 = 0.881 9 (NP) ? 0.899 9 (TBP) ? 0.7039 (NeP) ? 0.639 9 (PP), indicating that theweight of NeP was greater than that of PP in thefirst principal component (0.703 vs. 0.639). Thecommon factor (CF) of pain was calculated witha rotated component matrix, indicating thatthere are three major dimensions of pain in ASpatients: CF 1 represents NP and TBP, CF 2represents peripheral pain, and CF 3 represents

1470 Pain Ther (2021) 10:1467–1479

NeP. CF analysis showed that NeP was a rela-tively independent type of AS pain (Tables 2, 3).

3. Use of SEM: SEM was used to analyze theimpact of NeP on disease activity and psychol-ogy. BASDAI and ASDAS-CRP were employed toassess the disease activity index, while HospitalAnxiety and Depression Scale-Anxiety (HAD-A)and Hospital Anxiety and Depression Scale-De-pression (HAD-D) were used to evaluate thepsychological indexes of patients. SEM wassuccessfully established with a probability levelof 0.227, a ratio of Chi-square to degree offreedom (CMIN/DF) of 1.413, a comparative fitindex (CFI) of 0.996, a normed fit index (NFI) of0.987, and a root mean squared error ofapproximation (RMSEA) of 0.048. The SEMresults showed that PDQ could alter diseaseactivity (b = 0.62, P\0.001), which in turnaffected psychological status (b = 0.42,P\ 0.001) (Fig. 2).

Table 1 Clinical data of AS patients in different groups

PDQ £ 12 (n = 113) 12 < PDQ < 19 (n = 55) PDQ ‡ 19 (n = 14) P value

Sex (M/F) 102/11 53/2 8/6 0.6872

Age (years) 36.96 ± 11.60 36.36 ± 8.88 37.43 ± 10.78 0.9228

Duration 10.94 ± 8.87 8.67 ± 6.07 14.36 ± 9.24 0.0458*

NSARDs 95/113 54/55 14/14 0.7703

NP 2.25 ± 2.85 5.34 ± 4.55 5.87 ± 3.02 \ 0.0001****

TBP 2.23 ± 2.62 5.54 ± 4.92 5.85 ± 2.48 \ 0.0001****

PP 1.25 ± 1.79 2.44 ± 2.40 4.54 ± 2.54 \ 0.0001****

CRP 12.75 ± 18.12 14.41 ± 11.79 16.77 ± 11.36 0.6057

ASDAS-CRP 1.29 ± 0.76 2.09 ± 0.70 2.60 ± 0.81 \ 0.0001***

BASDAI 1.71 ± 1.56 3.72 ± 1.88 5.16 ± 1.95 \ 0.0001****

HAQ 4.39 ± 5.01 8.0 ± 10.65 8.96 ± 9.49 0.0033**

HAD-A 4.46 ± 3.30 6.23 ± 3.21 7.50 ± 2.47 0.001***

HAD-D 5.48 ± 3.81 6.63 ± 3.30 9.00 ± 3.32 0.0016*

BASDAI-fatigue 2.58 ± 2.40 3.87 ± 2.39 5.67 ± 2.31 \ 0.0001****

PDQ pain detection questionnaire, NP nocturnal pain, TBP total back pain, PP peripheral pain, CRP C-reactive protein,ASDAS-CRP ankylosing spondylitis disease activity score-CRP, BASDAI bath assessment of ankylosing spondylitis diseaseactivity index, HAQ health assessment questionnaire, HAD-A hospital anxiety and depression scale-anxiety, HAD-D hospital anxiety and depression scale-depressionData are expressed as the mean ± standard deviation (SD), P value comparison between the three groups, ****P\ 0.0001,***P\ 0.001, **P\ 0.01, *P\ 0.05

Table 2 Principal component analysis; component matrix

C1 C 2 C3 C 4

PDQ 0.703 0.422 - 0.572 0.001

NP 0.881 - 0.411 0.045 0.229

TBP 0.899 - 0.361 0.070 - 0.236

PP 0.639 0.610 0.468 0.014

Method of extraction: principal component analysisFour components were extractedC component, PDQ pain detection questionnaire,NP nocturnal pain, TBP total back pain, PP peripheralpain

Pain Ther (2021) 10:1467–1479 1471

4. Pain improvement after biological treat-ment: Of the 63 AS patients who used etaner-cept for 12 weeks, PDQ was B 12 in 32 patients,and PDQ was[ 12 in the remaining 31 patients.There were no significant differences in sex(male) (mean ± SD: 26/32 vs. 27/31,P = 0.6059), age (mean ± SD: 37.97 ± 12.83 vs.36.61 ± 9.56, P = 0.6254), and disease duration(mean ± SD: 12.90 ± 10.77 vs. 11.22 ± 8.79,P = 0.5592) between two groups. These resultssuggested that despite the degrees of NP, TBPand PP were significantly decreased after medi-cation administration, PDQ was not signifi-cantly decreased (mean ± SD: 10.60 ± 6.85 vs.9.98 ± 6.40 P = 0.0671). Subgroup analysisrevealed that PDQ was decreased significantly inAS patients with PDQ[12 (mean ± SD:17.06 ± 2.40 vs. 15.55 ± 3.69, P = 0.0059) anddid not show a significant decrease in ASpatients with PDQ B 12 (mean ± SD:

4.34 ± 2.47 vs. 4.59 ± 2.79, P = 0.5076)(Table 4).

5. Detection of neurotransmitters in ASpatients: Of the 20 AS patients in the third partof the study, PDQ was[ 19 in six patients andPDQ B 19 in 14 patients. The characteristic andclinical data of the patients and healthy con-trols (HC) are shown in Table 5. The nore-pinephrine (NE) concentration in patients withPDQ[19 was significantly higher than that inpatients with PDQ B 19 and HC (0.21 ± 0.06vs. 0.13 ± 0.05 vs. 0.07 ± 0.02, P\0.001).There was no significant difference in otherneurotransmitter concentrations.

DISCUSSION

Our research indicates that AS-associated painwas not merely a kind of IP but also involvedNeP. TNF inhibitors are seemingly ineffective atimproving AS-associated NeP. The change in NE

Table 3 Principal component analysis; rotated compo-nent matrix

C 1 C 2 C 3 C4

PDQ 0.224 0.213 0.951 0.006

NP 0.949 0.139 0.201 - 0.211

TBP 0.928 0.185 0.201 0.255

PP 0.176 0.963 0.205 0.006

Method of extraction: principal component analysisMethod of rotation: Caesar normal maximum variancemethodRotation converged in 5 iterationsP\ 0.01 by Bartlett’s test; the results of first principalcomponent calculation were as follows:F1 = 0.881 9 (nocturnal pain) ? 0.899 9 (total backpain) ? 0.703 9 (neuropathic pain) ? 0.639 9 (periph-eral pain)The weight of neuropathic pain was greater than periph-eral pain in the first principal component (0.703 vs. 0.639).Common factors (CF) of pain calculated by rotatedcomponent matrix analysis: CF 1 represents nocturnalpain and low back pain; CF 2 represents peripheral pain;and CF 3 represents PDQC component, PDQ pain detection questionnaire,NP nocturnal pain, TBP total back pain, PP peripheralpain

Fig. 2 Structural equation modeling. Structural equationmodeling (SEM) on the impact of neuropathic pain ondisease activity and psychology. BASDAI and ASDAS-CRP were used as the disease activity index, and HAD-Aand HAD-D were used as the psychological index. SEMwas successfully established (probability level = 0.227;ratio of Chi-square to degree of freedom [CMIN/DF] = 1.413; comparative fit index [CFI] = 0.996;normed fit index [NFI] = 0.987; and root mean squarederror of approximation [RMSEA] = 0.048). According toSEM, PDQ could alter the disease activity (b = 0.62,P\ 0.001), and the disease activity could influence thepsychological status (b = 0.42, P\ 0.001)

1472 Pain Ther (2021) 10:1467–1479

Table

4Changes

intheclinicaldata

in63

patientswho

weregivenetanercept

for6months

PDQ

£12

(n=32)

PDQ

>12

(n=31)

Overall

Baseline

phase

After

drug

administration

Pvalue

Baseline

phase

After

drug

administration

Pvalue

Baseline

phase

After

drug

administration

Pvalue

PDQ

4.34

±2.47

4.59

±2.79

0.5076

17.06±

2.40

15.55±

3.69

0.0059**

10.60±

6.85

9.98

±6.40

0.0671

NP

2.85

±3.41

1.63

±1.88

0.0044**

6.61

±5.20

3.42

±2.30

\0.0001****

4.70

±4.75

2.49

±2.26

\0.0001****

TBP

2.62

±3.11

1.73

±1.85

0.0120*

7.01

±3.32

3.32

±2.30

\0.0001****

4.78

±5.04

2.50

±2.21

\0.0001****

PP1.55

±2.28

1.25

±1.95

0.2161

3.23

±2.63

1.72

±2.40

\0.0001****

2.38

±2.58

1.48

±1.99

\0.0001****

CRP

12.92±

17.23

7.40

±11.47

0.0017**

14.98±

10.88

6.41

±3.91

\0.0001****

13.93±

14.38

6.91

±8.56

\0.0001****

BASD

AI

1.88

±1.66

1.56

±1.46

0.1902

4.39

±1.89

2.74

±1.40

\0.0001****

3.12

±2.17

2.14

±1.54

\0.0001****

ASD

AS

1.43

±0.90

1.02

±0.09

0.0007***

2.33

±0.74

1.59

±0.80

\0.0001****

1.87

±0.94

1.30

±0.79

\0.0001****

HAQ

1.87

±1.33

0.86

±0.88

0.0001****

2.27

±1.47

1.51

±1.13

\0.0001****

2.07

±1.40

1.18

±1.05

\0.0001****

HAD-A

4.43

±3.32

2.87

±2.89

0.0009***

6.74

±2.97

4.80

±3.02

0.0004****

5.57

±3.33

3.82

±3.09

\0.0001****

HAD-D

6.00

±3.44

4.00

±2.79

0.0016**

7.19

±3.26

4.74

±3.01

\0.0001****

5.73

±7.43

3.63

±5.09

\0.0001****

BASD

AI-

fatigue

2.57

±2.49

1.79

±1.84

0.0316*

3.77

±5.43

2.87

±4.51

0.0143*

2.92

±4.22

2.16

±3.29

0.001**

Dataareexpressedas

themean±

standard

deviation(SD);Pvaluerepresents

comparisonbefore

andafterdrug

administration,

****P\

0.0001,***P

\0.001,

**P\

0.01,*P\

0.05

PDQ

pain

detectionquestionnaire,NPnocturnalpain,TBPtotalback

pain,PP

peripheral

pain,CRPC-reactiveprotein,

ASD

AS-CRPankylosing

spondylitis

diseaseactivity

score-CRP,

BASD

AIbath

assessmentof

ankylosing

spondylitis

diseaseactivity

index,

HAQ

health

assessmentquestionnaire,

HAD-A

hospital

anxietyanddepression

scale-anxiety,HAD-D

hospitalanxietyanddepression

scale-depression

Pain Ther (2021) 10:1467–1479 1473

concentrations in the peripheral blood of ASpatients with NeP suggests that interferencewith neurotransmitter actions is a promisingnew approach to the treatment of AS-associatedNeP.

The main symptom of AS is pain, which iscurrently recognized as one type of IP [12].Thus, previous studies and the development ofnew anti-AS medications have mainly focusedon blocking inflammatory factors [13], [14],[15]. Given the large number of outpatients andlack of communication time between physi-cians and patients in China and the actualclinical situation in China, both physicians andpatients usually pay attention to laboratorytesting and imaging findings, inevitably leadingto overlooking pain and other subjectivesymptoms. However, it has been commonlyobserved that some AS patients complain ofpain even when inflammatory indexes such asESR and CRP are within the normal ranges or

biologics have been administered. It seemsincomplete and biased to entirely attribute theclinical symptoms of AS to IP. Increased studiesin recent years have found that pain in ASpatients is not always correlated with inflam-mation [16], [17]. In addition, this kind of painoften has the characteristics of NeP, includingnumbness and pricking sensations. Freynhagenet al. investigated more than 8000 patients withchronic pain and found that approximatelyone-third had pain of a neuropathic nature [18].Using head MRI, Wu et al. demonstrated NeP inAS patients and revealed that the correspondingabnormality in the grey matter was correlatedwith clinical symptoms [19].

In the clinic, fibromyalgia is a neuropathicpain syndrome and is common in patients withhistories of inflammatory diseases with symp-toms of chronic pain, including Sjogren’s syn-drome, systemic lupus erythematosus (SLE), orrheumatoid arthritis (RA). However, for AS

Table 5 Changes of neurotransmitter concentrations in peripheral blood of 20 AS patients and ten healthy controls

PDQ > 19 (n = 6) PDQ £ 19 (n = 14) Control (n = 10) P

Sex (M/F) 4/2 13/1 8/2 0.3338

Age 42.67 ± 4.27 36.57 ± 2.72 0.21 ± 0.06 0.2394

Duration 18.67 ± 2.47 11.94 ± 2.19 0.0887

CRP 5.02 ± 2.60 8.09 ± 6.79 0.3028

BASDAI 4.27 ± 1.89 2.15 ± 1.17 0.0064**

NE 0.21 ± 0.06 0.13 ± 0.05 0.07 ± 0.02 \ 0.001***

5HT 22.62 ± 9.65 20.50 ± 17.85 19.96 ± 10.01 0.9338

Gly 110.8 ± 21.37 96.61 ± 25.24 95.32 ± 34.52 0.5223

Glu 16.64 ± 7.32 29.83 ± 29.05 19.66 ± 5.05 0.3277

GABA 587.7 ± 19.01 629.0 ± 336.0 523.4 ± 135.4 0.6213

5HIAA 2.21 ± 0.97 3.97 ± 3.87 2.62 ± 0.67 0.3277

KYN 78.35 ± 25.35 83.87 ± 44.80 69.79 ± 18.05 0.4845

TRP 1,860 ± 402.7 2,067 ± 482.0 2,008 ± 446.7 0.6528

Data are expressed as the mean ± standard deviation (SD); P value represents comparison between the three groups,***P\ 0.001, **P\ 0.01, *P\ 0.05CRP C-reactive protein, BASDAI bath assessment of ankylosing spondylitis disease activity index, NE norepinephrine,5HT serotonin, Gly glycine, Glu glutamic acid, GABA c-aminobutyric acid, 5HIAA 5-hydroxyindoleacetic acid, KYNkynurenine, TRP tryptophan

1474 Pain Ther (2021) 10:1467–1479

patients, the evidence is lacking and contro-versial [20]. Previous studies have reported thehigh prevalence of fibromyalgia in patients withAS [21], [22]. In contrast, a recent study statedthat compared with normal people, the inci-dence of fibromyalgia did not increase inpatients with AS [23]. In the Chinese popula-tion, so far, there is no epidemiological data onfibromyalgia syndrome. As a neuropathic pain(Nep) syndrome, fibromyalgia contributes tomultifocal pain. Because of the dysregulatedfunction in the central nervous system andamplification of the sense of pain, symptomssuch as musculoskeletal pain, visceral pain, andchronic headaches are often observed inpatients [24]. In fibromyalgia patients, changesin the number of inflammatory cytokines havebeen widely reported, and the role of neuro-genic inflammation has been thought to play apotential role between inflammatory disorderand the development of fibromyalgia [25].Therefore, the patients with fibromyalgia wereexcluded at enrollment to reduce the bias inthis study. Despite exclusion of fibromyalgia, atotal of 14 patients (7.7%) still showed probableNep with PDQ scores of C 19, which furtherconfirmed the important role of Nep in the painof AS patients and needed attention in clinical.

Diagnosis of a neuropathic component ischallenging because there is currently no uni-versally accepted gold standard. Previous stud-ies have confirmed that the PainDETECTquestionnaire (PDQ), Douleur Neuropathiqueen 4 Questions (DN4), and Leeds Assessment ofNeuropathic Symptoms and Signs (LANSS) areall reliable screening tools for neuropathic pain(Nep) and have been validated for the use inpopulations with NeP. All of these question-naire tools have also been validated as self-re-port items and are therefore suitable for use in apostal/online survey research [5], [26]. Amongthe three questionnaires, the PDQ was trans-lated into and validated in multiple languages.PDQ is nowadays used for clinical and researchpurposes [27]. A study in Chinese Nep popula-tions showed that the Chinese version of PDQscale had a good retest reliability and validity(intraclass correction coefficient [ICC] = 0.973),which can be applied to the clinical screening ofChinese patients with Nep [28]. The PDQ is self-

administered questionnaire, specifically devel-oped and validated for use in patients with lowback pain with sensitivity and specificity of 85and 80%, respectively, with a positive predictivevalue of 83% [5]. Cronbach’s a coefficient of thePDQ was analyzed to determine the internalconsistency of the Chinese PDQ in assessingfatigue in AS patients. The coefficient of thePDQ in AS was 0.92, suggesting that the Chi-nese PDQ had a relatively high internal consis-tency and reliability. It is feasible to apply aChinese PDQ in practice to assess neuropathicpain components.

Despite the importance of NeP in ASpatients, the prevalence and characteristics ofNeP components in patients with AS in clinicalpractice is limited. The present study con-tributes to fill this gap. In the present study,approximately one-third of 182 AS patients hadlikely or uncertain NeP. We extrapolate that theNep component in AS is underdiagnosed,underestimated in importance, and under-treated. Borman et al. used the LANSS and DN4to assess pain in 58 AS patients and found thatmore than 50% had NeP [29]. Choi et al. usedthe PDQ to assess 105 AS patients and reportedthat 15 (14.2%) had NeP. All of these findingssuggest that NeP commonly occurs in ASpatients [30]. In addition, the PCA of pain inour study showed that the weight of NeP wasgreater than that of PP. CF analysis demon-strated that pain in AS consists of three rela-tively independent dimensions, which arerepresented by IP (NP and TBP), NeP, and PP.This finding suggests that NeP is an importantcomponent of AS pain. The SEM results alsosuggested that NeP affects the disease severity ofAS, which can further alter the psychologicalstatus of AS patients. In summary, these find-ings indicate that the incidence of NeP in ASpatients is much higher than we expectedbefore and NeP plays a critical role in AS diseaseseverity, thereby further affecting the psycho-logical status of AS patients.

Studies on the therapeutic effect of TNF-a onNeP have revealed meaningful results. In thepast, some studies have reported that local orspinal administration of medication thatantagonize TNF-a activity attenuates pain inneuropathic animal models [31], [32]. Other

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studies found that mechanical allodynia in a ratmodel of central neuropathic pain, produced byT13 spinal cord hemisection, was attenuated bythe immediate intrathecal administration ofetanercept 1–4 weeks after injury to the spinalcord [33]. To the best of our knowledge, how-ever, we are unaware of any randomized con-trolled clinical trials of infliximab or etanerceptfor the treatment of other forms of NeP. TNFinhibitors are currently the most effectivemedication for AS. Our study demonstrated thataxial pain, PP, and various inflammatoryindexes were improved significantly in ASpatients who were administered etanercept for12 weeks, whereas PDQ was not improved sta-tistically, suggesting that NeP poses a particulartreatment challenge to physicians. At present,the therapeutic field of AS is developing rapidlyand there are also biologic medicines such asinterleukin-17 (IL-17) and Janus kinase (JAK)inhibitors. It was reported that interleukin-17(IL-17) can regulate neuron-glial communica-tions, synaptic transmission, and Nep afterchemotherapy [34]. AG490 (tyrosine kinaseinhibitors) is effective for reducing oxaliplatin-induced acute Nep. This new function of AG490is anti-neuroinflammatory and probably acts byinhibiting the JAK/STAT3 signaling; however,the detailed and precise mechanism still needsfurther investigation [35].

In order to better understand the pathogen-esis of Nep in AS patients, we further consultedthe related literature. Several studies havereported that the various endogenous trans-mitters (noradrenaline, dopamine, glutamate,gamma-aminobutyric acid [GABA], serotonin,met- and leu-enkephalins, b-endorphin, dynor-phins, cannabinoids, adenosine triphosphate[ATP]) and various receptors (a2, l, etc.) have aclose correlation with neuropathic pain [36],[37]. We detected eight neurotransmitters in theperipheral blood of 20 AS patients and foundthat the serum NE concentrations in AS patientswith higher PDQ were significantly elevated.Both NE and 5HT are pain-related neurotrans-mitters that participate in regulating bothalgesic and analgesic processes. Peripherally,these neurotransmitters are algesic factors thatexert a regulatory effect on local neurocytes viasecond messengers such as calcium ions or

cyclic nucleotides or through a paracrine path-way producing pain by the stimulation of sen-sory nerve endings. Detection of theconcentration of algesic factors in peripheralblood can, to some extent, reflect the degree ofpain [36]. Based on this finding, we are usingpregabalin to treat NeP in AS patients, and therelated data are still being collected.

There are some limitations in this study.Firstly, the sample size was relatively small.Secondly, we only detected neurotransmittersin the peripheral blood of a limited number ofAS patients. We intend to further expand thesample size in our ongoing studies and use headMRI to investigate the structural or functionalchanges in the pain-related regions of the cen-tral nervous system.

CONCLUSIONS

In summary, NeP is a common occurrence in ASpatients. It is an important component and oneof the three dimensions of AS pain. TNF inhi-bitors do not appear to be as effective asexpected in improving AS-associated NeP. TheNE concentrations in the peripheral blood of ASpatients with NeP complications are signifi-cantly elevated, suggesting that interferencewith neurotransmitter activity may be apromising new treatment for AS-associated NeP.

Declarations

Funding The study and the journal’s RapidService Fee were supported by the NationalNatural Science Foundation of China (GrantNo. 31821003), National Key Research andDevelopment Project (Grant No.2018AAA0100302), Shanghai Municipal KeyClinical Specialty (shslczdzk02602), andShanghai Science and Technology Develop-ment Funds (2020-SH-XY-2).

Authorship All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

1476 Pain Ther (2021) 10:1467–1479

Authorship Contributions Conception anddesign of the study: HJX, LZ and TL. Acquisi-tion, analysis and interpretation of data: XW,HJL, LL, LYY, JY, JZ, and XWW. Drafting thearticle and revising it critically for importantintellectual content: LZ, TL, XW, HJL, and HJX.Final approval of the article: LZ, TL, XW, HJL,LL, LLY, JY, JZ, XWW, JYB, and HJX.

Disclosures Ling Zhou, Ting Li, Xin Wu,Hongjuan Lu, Li Lin, Lingying Ye, Jian Yin, JuanZhao, Xiuwen Wang, Jianye Bian, and Huji Xudeclare that they have nothing to disclose.

Compliance with Ethics Guidelines The studywas conducted according to the Helsinki Dec-laration and approved by the ethics communityof Shanghai Changzheng Hospital (ID:2017SL046). All patients gave written informedconsent. Participants included in our studyprovided consent for publication if any identi-fying information is included in themanuscript.

Data Availability The datasets generatedduring and/or analyzed during the currentstudy are available from the correspondingauthor on reasonable request. We thank all theparticipants participating in our research.

OPEN ACCESS

This article is licensed under a Creative Com-mons Attribution-NonCommercial 4.0 Interna-tional License, which permits any non-commercial use, sharing, adaptation, distribu-tion and reproduction in any medium or for-mat, as long as you give appropriate credit tothe original author(s) and the source, provide alink to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commonslicence, unless indicated otherwise in a creditline to the material. If material is not includedin the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, you

will need to obtain permission directly from thecopyright holder. To view a copy of this licence,visit http://creativecommons.org/licenses/by-nc/4.0/.

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