ABSTRACT
Objective
To investigate the central sensitization (CS) in patients with autoimmune connective tissue diseases (ACTDs) and its relationship with disease activity, laboratory findings, medical treatments, organ involvements, and comorbidity.
Methods
One hundred and eleven patients with ACTDs and 40 healthy individuals were included. All patients were divided into three groups in terms of their diseases: Sjögren's syndrome (SS), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). The CS was assessed using the central sensitization inventory (CSI‐A and CSI‐B scores). The disease activity, laboratory findings, medical treatments, organ involvements, and comorbidity of all patients were evaluated.
Results
Overall, 41.4% patients with ACTDs had CS. SS group had the highest CS positivity (n = 21, 58.3%) compared to the RA (n = 14, 36.8%) and SLE (n = 11, 29.7%) groups. The SS group had a significantly higher CSI‐A score (p < 0.016) than the RA and SLE group, which had similar scores. CSI‐A (p = 0.008, r = −0.63) and CSI‐B (p = 0.001, r = −0.76) scores were moderately to high correlated with vitamin D3 levels in SLE group. CSI‐B score was moderately correlated with folic acid levels (p = 0.03, r = 0.50) and TSH (p = 0.005, r = 0.55) in SS group. The CSI‐A score ≥ 40 subgroup had more female gender, frequency of COPD or asthma, more coexisting fibromyalgia, higher VAS score, more common exocrine gland involvement, and higher corticosteroid dose compared to the CSI score < 40 subgroup.
Conclusions
CS is commonly seen in patients with ACTDs, especially in SS. CS is associated with vitamin D3, folic acid, and TSH levels in ACTD subgroups and the patients with clinical CS have a specific profile.
Keywords: central nervous system sensitization, chronic pain, rheumatoid arthritis, Sjögren's syndrome, systemic lupus erythematosus
1. Introduction
Central sensitization (CS) is an increased responsiveness of nociceptive neurons in the central nervous system (CNS) to their normal or subthreshold peripheral input [1]. The CNS becomes more sensitive to input through structural, functional, and chemical changes [2]. With or without continuing peripheral input, CS may be maintained, and these alterations in the CNS may eventually lead to a persistent, heightened state of neuronal reactivity [3, 4]. CS involves an amplification of neural signaling within the CNS that results in pain hypersensitivity [5]. This amplification frequently results in chronic, broad, and migratory pain, chronic fatigue, sensory hypersensitivity, and many other symptoms. CS is associated with several medical diagnoses, including low back pain, osteoarthritis (OA), whiplash, and fibromyalgia; however, it currently cannot be directly determined clinically; certain signs and symptoms may suggest its presence [6].
Chronic pain is one of the most common symptoms in rheumatic diseases, and it has a negative effect on sleep, mood, and energy, requiring attention to the global suffering of patients [7]. Recent understanding of the pathophysiology of rheumatic pain invokes the interplay of the nociceptive mechanisms driven by local tissue factors and the neurogenic responses that sustain chronic pain [8]. Nociceptors are activated or sensitized by inflammatory mediators such as bradykinin, prostaglandins, and nerve growth factor, as well as pro‐inflammatory cytokines such as tumor necrosis factor‐α, interleukin‐1β and pro‐inflammatory chemokines. As in immune cells, cytokines and chemokines released by nociceptors can rapidly regulate resident immune cells and attract circulating cells to the area of local inflammation that engage primary afferents and cell bodies in the nerve and dorsal root ganglion. The neuropathic and nociceptive mechanisms are associated with the mixed nature of pain in autoimmune rheumatic diseases and may lead to CS [9, 10, 11, 12, 13].
The pain in rheumatic diseases is maladaptive, and the pathogenesis of pain may be inflammatory and/or nociceptive [14]. While different medical approaches utilized in controlling the disease and disease activity provide significant gains to the patient, they may not adequately treat disease‐related pain, fatigue, sleep disturbance, anxiety, and depression [14]. It is well known that chronic inflammation in rheumatic diseases may trigger both peripheral and central modifications of pain pathways. The high prevalence of CS in patients with rheumatoid arthritis (RA) and spondyloarthropathies despite biologic therapy suggests that inflammation may not be the sole cause of pain and that additional pain mechanisms, such as pain perception and CS, may play a role in the persistence of pain [15, 16].
CS has recently been recognized as a possible underlying pathophysiological mechanism of chronic pain in different rheumatic diseases such as osteoarthritis, spondyloarthropathy, rheumatoid arthritis, and fibromyalgia. However, little is known about CS in patients with autoimmune connective tissue diseases (ACTDs) such as systemic lupus erythematosus (SLE) and Sjögren's disease (SS). The purpose of the study was to investigate the role of CS in patients with ACTDs and how it relates to disease activity, coexisting fibromyalgia, and laboratory findings. It is hypothesized that (1) considering inflammatory and nociceptive responses in these patients, the CS would increase among ACTD patients (2) the disease activity would correlate CS scores with coexisting fibromyalgia or laboratory signs; and (3) CS scores would be higher in ACTDs compared to healthy individuals.
2. Methods
2.1. Study Design
The comparative cross‐sectional study was approved by the Institutional Review Board of the authors' affiliated institutions (Ankara City Hospital, ID. E2‐22‐1510). Written informed consent was obtained from all patients, and all procedures were in accordance with the Declaration of Helsinki. The data were obtained in the xxx Hospital Department of Rheumatology between April 2022 and October 2022.
2.2. Participants
ACTDs patients with chronic musculoskeletal pain related to disease were included and were divided into three groups in terms of their diseases: Sjögren's syndrome (SS), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). As SS, RA and SLE are the more common autoimmune multisystem rheumatic disorders, these diseases are included in this study. Inclusion criteria were age ranged from 18 to 65 years; diagnosed with SS, RA, or SLE for at least 1 year; had chronic musculoskeletal pain for more than 3 months associated with SS, RA, or SLE; and had literacy to answer a questionnaire. Patients with any cardiovascular disease (history of acute myocardial infarction, heart failure, etc.), neurological diseases, oncologic diagnosis or history, medication use for neuropathic pain, neuropsychiatric medical treatment, medical treatment for fibromyalgia, chronic addiction to alcohol, and pregnancy were excluded from the study. Age‐ and BMI‐matched healthy participants were included as healthy control group (HCs). Inclusion criteria for HCs were age 18–65 years of age and no self‐reported chronic pain. Participants with more than 3 months of pain, orthopedic surgery in the last year, psychiatric disorders, neuropsychiatric medical treatment, and fibromyalgia were excluded (Figure 1).
FIGURE 1.
Flow chart of the study.
Participants who met the inclusion criteria were selected from the target population using probable simple random sampling. In this method, participants were assigned numbers, and those to be sampled were chosen using a random number table.
2.3. Measurements
Sociodemographic data, disease duration, comorbidities, smoking history, regular exercise habits, organ involvement, and medications were recorded. Routine laboratory findings such as erythrocyte sedimentation rate (ESR) (mm/h), C‐reactive protein (CRP) (mg/L), hemoglobin (g/dL), vitamin D3 (nmol/L), folic acid (ng/mL), vitamin B12 (ng/L), ferritin (μg/L), and TSH (mIU/L) were obtained on the day of the assessment.
2.3.1. Pain Intensity
The severity of the pain was assessed with the visual analog scale (VAS). The 100‐mm horizontal line was defined as 0 “no pain” and 100 “very severe pain”, and the patients were asked to mark a line indicating their musculoskeletal pain related to ACTDs disease, and then, the line was measured in millimeters [17].
2.3.2. Disease Activity
Disease activity was determined by calculating the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) for SS patients, the Disease Activity Score with 28‐joint count and C‐reactive protein (DAS‐28 CRP) score for RA patients, and the Systemic Lupus Erythematosus Disease Activity Index‐2K (SLEDAI‐2K) score for SLE patients. The ESSDAI score includes 12 organ‐specific domains, each representing a different area of disease involvement. The ESSDAI score ranges from 0 to 118, with higher scores indicating more active disease [18]. The DAS‐28 CRP combines the assessment of 28 tender and swollen joints, the patient's global assessment of disease activity, and CRP levels in the blood. The DAS‐28 CRP score ranges from 0 to 10, with higher values indicating greater disease activity [19]. The SLEDAI evaluates 24 different clinical and laboratory parameters, including symptoms, physical findings, and laboratory test results. Each parameter is assigned a score based on its severity or presence, and the scores are summed to obtain the overall SLEDAI‐2K score. The total score can range from 0 to 105, with higher scores indicating more active disease [20].
2.3.3. Central Sensitization
The presence and severity of central sensitization were assessed with the Central Sensitization Inventory (CSI), which is a questionnaire used to assess individuals with chronic pain. The Central Sensitization Inventory (CSI) is a self‐reported tool to assess symptoms of CS and has been widely adopted into scientific research and clinical practice. The CSI consists of two parts; the first part (CSI‐A) contains 25 items investigating emotional and somatic disorders associated with central sensitization. Each response is scored between 0 and 4, and the total score is obtained as 0–100. High scores indicate central sensitization symptoms of increasing severity. The second part of the scale (CSI‐B) investigates diagnosed disorders that may be related to central sensitization, such as restless leg syndrome, chronic fatigue syndrome, fibromyalgia syndrome, temporomandibular joint problems, migraine, irritable bowel syndrome, anxiety, and depression [21]. The CSI‐B section was assessed by the same physician (H.A) who was involved in the study. The cut‐off point of the CSI is 40 points. The Turkish validity and reliability study of the scale were conducted by Düzce et al. [22].
2.4. Statistical Analysis
A priori sample size analysis was performed with G Power software (Version 3.1.9.2, Franz Faul, University of Kiel, Kiel, Germany). CSI‐A score was determined as the primary outcome measure in agreement with the study by Guler, Celik and Ayhan [23] (mean: 36.36, n1: 42; mean: 38.43, n2: 56; mean: 43.6, n3: 45; mean: 58.92, n4: 50; blended SD: 15.5). The sample size of at least 80 individuals was found to have a power of 0.80, an effect size of 0.40, and an alpha value of 0.05 (two‐tailed). IBM SPSS (Statistical Package for the Social Sciences, ver. 22.0) was used for statistical analyses. Visual (histograms, probability plots) and analytical methods (Kolmogorov–Smirnov test) were performed to determine whether variables were normally distributed. The relationship among pain, disease activity, and central sensitization was evaluated with Spearman's correlation analysis due to non‐parametric conditions. The size of the correlation coefficient was considered to be very high (0.90–1.00), high (0.70–0.89), moderate (0.50–0.69), low (0.30–0.49), and negligible (0–0.29) [24]. A one‐way ANOVA or Kruskal–Wallis test was used to compare groups (SS, RA, and SLE). The Levene test was employed to assess the homogeneity of variances. Post hoc comparisons were performed with Tukey's test. If homogeneity was absent, the Welch F‐test was used. In the pairwise comparison, p value < 0.016 was considered significant. Statistical significance was considered as p value < 0.05.
3. Results
The demographic and clinical features of patients with ACTDs and HCs are shown in Table 1. The majority of patients (n = 97, 87.4%) had joint involvement, followed by exocrine gland involvement (n = 27, 24.3%) and skin involvement (n = 22, 19.8%). There were significant among‐group differences in terms of pain intensity (p < 0.001) and CRP (p = 0.006). The median ESSDAI score was 2 (range: 0–3) in the SS group, the median DAS‐28 CRP score was 3.2 (range: 2.8–3.8) in the RA group, and the median SLEDAI‐2K score was 4 (range: 2–6).
TABLE 1.
Demographic and clinical features of patients with ACTDs and healthy controls.
| ACTDs overall (n = 111) | SS (n = 36) | RA (n = 38) | SLE (n = 37) | HCs (n = 40) | p a/b | |
|---|---|---|---|---|---|---|
| Age (year), mean (SD) | 48.8 (11.2) | 49.5 (10.8) | 51.2 (12.7) | 45.7 (9.5) | 47.3 (8.9) | 0.138 |
| Female, n (%) | 93 (83.8) | 30 (83.3) | 28 (73.7) | 35 (94.6) | 30 (75) | 0.074 |
| BMI (kg/m2), mean (SD) | 27.7 (5.4) | 27.7 (5.1) | 28.6 (5.8) | 26.7 (5.1) | 26.8 (4.9) | 0.384 |
| Disease duration (year), median (IQR) | 3 (2–14) | 3 (2–3) | 9 (2–21) | 2 (1–8) | — | 0.307 |
| History of smoking, n (%) | ||||||
| None | 80 (72.1) | 29 (80.6) | 21 (55.3) | 30 (81.1) | 25 (62.5) | |
| Ex‐smoker | 7 (6.3) | 4 (11.1) | 3 (36.8) | 0 (0) | 5 (12.5) | 0.574 |
| Active | 24 (21.6) | 3 (8.3) | 14 (7.9) | 7 (18.9) | 10 (25) | |
| Pack‐year, median (IQR) | 9.5 (5–20) | 15 (3–45) | 10 (6–27.5) | 5 (3–15) | 13.5 (12–16) | 0.496 |
| Regular exercise habits n (%) | 27 (24.3) | 7 (19.4) | 14 (36.8) | 6 (16.2) | 10 (25) | 0.081 |
| Comorbidity n (%) | ||||||
| Diabetes mellitus | 11 (9.9) | 4 (11.1) | 5 (13.2) | 2 (5.4) | 3 (7.5) | 0.652 |
| Hypertension | 25 (22.5) | 10 (27.8) | 10 (26.3) | 5 (13.5) | 5 (12.5) | 0.194 |
| Coronary artery disease | 9 (8.1) | 4 (11.1) | 4 (10.5) | 1 (2.7) | 0 (0) | 0.096a |
| Thyroid disorder | 22 (19.8) | 9 (25) | 5 (13.2) | 8 (21.6) | 4 (10) | 0.245 |
| Malignancy | 4 (3.6) | 1 (2.8) | 3 (7.9) | 0 (0) | 0 (0) | 0.089 |
| Chronic renal failure | 5 (4.5) | 2 (5.6) | 0 (0) | 3 (8.1) | 2 (5) | 0.401 |
| COPD | 8 (7.2) | 2 (5.6) | 2 (5.3) | 4 (10.8) | 2 (5) | 0.706 |
| Osteoporosis | 5 (4.5) | 2 (5.6) | 1 (2.6) | 2 (5.4) | 0 (0) | 0.481 |
| Depression | 2 (1.8) | 0 (0) | 2 (5.3) | 0 (0) | 0 (0) | 0.110 |
| Organ involvement, n (%) | ||||||
| Joint | 97 (87.4) | 33 (91.7) | 38 (100) | 26 (70.3) | — | < 0.001 |
| Skin | 22 (19.8) | 6 (16.7) | 0 (0) | 16 (43.2) | — | < 0.001 |
| Lung | 12 (10.8) | 4 (11.1) | 2 (5.3) | 6 (16.2) | — | 0.311 |
| Cardiac | 5 (4.5) | 0 (0) | 1 (2.6) | 4 (10.8) | — | 0.06 |
| Renal | 18 (16.2) | 0 (0) | 0 (0) | 18 (48.6) | — | < 0.001 |
| Central nervous system | 3 (3.7) | 0 (0) | 0 (0) | 3 (8.1) | — | 0.046 |
| Exocrine gland | 27 (24.3) | 26 (72.2) | 1 (2.6) | 0 (0) | — | < 0.001 |
| Laboratory findings, median (IQR) | ||||||
| ESR (mm/h) | 18 (6–28) | 21 (6–29) | 11.5 (7–22) | 18 (7–29) | — | 0.500 |
| CRP (mg/L) | 3 (1–9) | 2 (1–3) | 6.5 (2–12) | 5 (1–8) | — | 0.006 |
| Hemoglobin (g/dL) | 12.8 (12–14.4) | 13 (12.3–14.2) | 13 (12.4–14.5) | 12.1 (11.6–13) | — | 0.133 |
| Vitamin D3 (nmol/L) | 39 (20–62) | 46 (20–62) | 28.5 (19–47.5) | 34 (20–69) | — | 0.435 |
| Folic acid (ng/mL) | 10 (7–12) | 10 (9–12) | 8 (5.5–12.5) | 11 (11–12) | — | 0.128 |
| Vitamin B12 (ng/L) | 344 (267–430) | 345 (262–424) | 317 (272–427) | 356 (325–455) | — | 0.427 |
| Ferritin (μg/L) | 27 (16–69) | 38 (24–69) | 25 (16–62) | 25 (12.5–74.5) | — | 0.707 |
| TSH (mIU/L) | 1.74 (0.89–3.2) | 2.11 (1.36–3.5) | 1.44 (0.8–2) | 1.41 (0.9–3.3) | — | 0.175 |
| Medications, n (%) | ||||||
| Methotrexate | 23 (20.7) | 0 (0) | 21 (55.3) | 2 (5.4) | — | < 0.001 |
| Leflunomide | 9 (8.1) | 0 (0) | 9 (23.7) | 0 (0) | — | < 0.001 |
| Hydroxychloroquine | 77 (69.4) | 27 (75) | 24 (63.2) | 26 (70.3) | — | 0.538 |
| Sulfasalazine | 4 (3.6) | 0 (0) | 4 (10.5) | 0 (0) | — | 0.019 |
| Colchicine | 8 (7.2) | 3 (8.3) | 5 (13.2) | 0 (0) | — | 0.084 |
| Corticosteroid | 61 (55) | 10 (27.8) | 26 (68.4) | 25 (67.6) | — | < 0.001 |
| Corticosteroid dose (mg), median (IQR) | 4 (2.5–4) | 4 (4–5) | 4 (2–4) | 4 (4–4) | — | 0.168b |
| Biological DMARD | 15 (13.5) | 0 (0) | 7 (18.4) | 8 (21.6) | — | 0.014 |
| Anti‐TNF | 7 (6.3) | 1 (2.8) | 3 (7.9) | 3 (8.1) | — | 0.376 |
| Regular NSAIDs | 6 (5.4) | 2 (5.6) | 2 (5.3) | 2 (5.4) | — | 0.996 |
| VAS (cm), mean (SD) | 4.7 (2.6) | 5.4 (1.9) | 5.0 (1.9) | 3.8 (3.5) | 1.1 (1.2) | < 0.001 |
| Disease activity, median (IQR) | ||||||
| ESSDAI | 2 (0–3) | |||||
| DAS‐28 CRP SLEDAI‐2 K | 3.2 (2.8–3.8) | 4 (2–6) | ||||
Abbreviations: ACTDs, autoimmune connective tissue diseases; COPD, chronic obstructive pulmonary disease; CRP, C‐reactive protein; DAS‐28 CRP, disease activity score with 28‐joint count and C‐reactive protein; ESR, erythrocyte sedimentation rate; ESSDAI, EULAR Sjögren's syndrome disease activity index; HCs, healthy controls; IQR, interquartile range; NSAIDs, non‐steroidal anti‐inflammatory drugs; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SLEDAI, systemic lupus erythematosus disease activity index; S, Sjögren's syndrome; TSH, thyroid‐stimulating hormone; VAS, visual analogue scale.
Note: Bold values indicate statistical significance at p < 0.05.
χ 2 test or Fisher exact test.
One‐way analysis of variance or Kruskal–Wallis test.
A comparison of the frequency and severity of CS among the groups is presented in Table 2. There were significant among‐group differences in the CSI‐A scores (p < 0.001), CSI‐B scores (p = 0.016), and CS positivity (p < 0.001). Patients with ACTDs had higher CSI‐A, CSI‐B scores, and CS positivity than the healthy group (p < 0.05). Post hoc analyses showed that the SS group had a significantly higher CSI‐A score (p < 0.016) than the RA and SLE group, which had similar scores. Approximately half of the patients with ACTDs (n = 46, 41.4%) were CS positive, and the SS group had the highest CS positivity (n = 21, 58.3%) compared to the RA (n = 14, 36.8%) and SLE (n = 11, 29.7%) groups. In terms of CSI‐related syndromes, significant differences among groups in the prevalence of fibromyalgia were evident. The prevalence of fibromyalgia was highest in the SS group (30.6%).
TABLE 2.
Comparison of the frequency and severity of central sensitization among the groups.
| ACTDs overall (n = 111) | SS (n = 36) | RA (n = 38) | SLE (n = 37) | HCs (n = 40) | ||
|---|---|---|---|---|---|---|
| CSI‐A (point), median (IQR) | 35 (24–51) | 43 (31–59) | 28 (21–49) | 32 (22–44) | 8 (4–11) | < 0.001 |
| CSI‐B (point), median (IQR) | 0 (0–1) | 0 (0–1) | 0 (0–1) | 0 (0–1) | 0 (0–0) | 0.016 |
| CSI positivity, n (%) | 46 (41.4) | 21 (58.3) | 14 (36.8) | 11 (29.7) | 0 (0) | < 0.001 |
| CSI‐related syndromes, n (%) | ||||||
| Restless leg syndrome | 9 (8.1) | 0 (0) | 4 (10.5) | 5 (13.5) | 2 (5) | 0.119 |
| Chronic fatigue syndrome | 6 (5.4) | 2 (5.6) | 1 (2.6) | 3 (8.1) | 0 (0) | 0.292 |
| Fibromyalgia | 18 (16.2) | 11 (30.6) | 6 (15.8) | 1 (2.7) | 0 (0) | < 0.001 |
| Temporomandibular joint disorder | 8 (7.2) | 2 (5.6) | 3 (7.9) | 3 (8.1) | 1 (2.5) | 0.700 |
| Migraine or tension headaches | 9 (8.1) | 0 (0) | 2 (5.3) | 7 (18.9) | 3 (7.5) | 0.024 |
| Irritable bowel syndrome | 9 (8.1) | 6 (16.7) | 1 (2.6) | 2 (5.4) | 1 (2.5) | 0.045 |
| Multiple chemical sensitivities | 2 (1.8) | 0 (0) | 0 (0) | 2 (5.4) | 0 (0) | 0.100 |
| Neck injury (including whiplash) | 1 (0.9) | 0 (0) | 1 (2.6) | 0 (0) | 0 (0) | 0.397 |
| Anxiety or panic attacks | 14 (12.6) | 3 (8.3) | 3 (7.9) | 8 (21.6) | 0 (0) | 0.012 |
| Depression | 9 (8.1) | 2 (5.6) | 3 (7.9) | 4 (10.8) | 0 (0) | 0.226 |
Abbreviations: ACTDs, autoimmune connective tissue diseases; CSI, central sensitization inventory; CSI‐A, the first part of central sensitization inventory; CSI‐B, the second part of central sensitization inventory; HCs, healthy controls; IQR, interquartile range; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SS, Sjögren's syndrome.
Note: Bold values indicate statistical significance at p < 0.05.
χ 2 test or Kruskal–Wallis test.
There was a significant correlation between DAS‐28 CRP and the CSI‐A scores in patients with RA (p = 0.022, r = 0.37) (Table 3). CSI‐A (p = 0.008, r = −0.63) and CSI‐B (p = 0.001, r = −0.76) scores were moderately to highly correlated with vitamin D3 in the SLE group. CSI‐B score was moderately correlated with folic acid (p = 0.03, r = 0.50) and TSH (p = 0.005, r = 0.55) in the SS group. CSI‐B score was lowly correlated with hemoglobin (p = 0.022, r = −0.37) in the RA group. The relationship between the CSI‐A and CSI‐B scores and laboratory findings is shown in Table 4.
TABLE 3.
Correlation analysis between the disease activity and the central sensitization scores.
| ESSDAI | DAS‐28 CRP | SLEDAI | ||
|---|---|---|---|---|
| CSI‐A | r | 0.169 | 0.372 | 0.270 |
| p value | 0.325 | 0.022 | 0.105 | |
| CSI‐B | r | −0.24 | 0.26 | 0.24 |
| p value | 0.15 | 0.11 | 0.15 | |
Abbreviations: CSI, central sensitization inventory; CSI‐A, the first part of central sensitization inventory; CSI‐B, the second part of central sensitization inventory; DAS‐28 CRP, disease activity score with 28‐joint count and C‐reactive protein; ESSDAI, EULAR Sjögren's syndrome disease activity index; SLEDAI, systemic lupus erythematosus disease activity index.
Note: Bold values indicate statistical significance at p < 0.05.
TABLE 4.
Correlation analysis between the central sensitization scores and laboratory finding.
| ESR | CRP | Hemoglobin | Vitamin D | Folic acid | Vitamin B12 | Ferritin | TSH | |||
|---|---|---|---|---|---|---|---|---|---|---|
| CSI‐A | ACTDs | R | −0.03 | −0.02 | 0.009 | −0.06 | 0.18 | 0.14 | 0.03 | 0.20 |
| p value | 0.74 | 0.78 | 0.922 | 0.66 | 0.15 | 0.25 | 0.80 | 0.10 | ||
| SS | R | 0.88 | −0.54 | −0.230 | 0.03 | 0.30 | 0.17 | −0.16 | 0.31 | |
| p value | 0.61 | 0.75 | 0.178 | 0.87 | 0.23 | 0.42 | 0.49 | 0.13 | ||
| RA | R | 0.20 | 0.10 | −0.234 | 0.19 | 0.27 | 0.31 | −0.15 | −0.12 | |
| p value | 0.21 | 0.54 | 0.158 | 0.46 | 0.18 | 0.11 | 0.48 | 0.56 | ||
| SLE | R | −0.29 | 0.00 | 0.252 | −0.63 | −0.03 | −0.12 | 0.33 | −0.22 | |
| p value | 0.07 | 0.95 | 0.132 | 0.008 a | 0.89 | 0.62 | 0.20 | 0.33 | ||
| CSI‐B | ACTDs | R | −0.01 | −0.73 | −0.118 | −0.28 | −0.04 | 0.19 | −0.08 | 0.19 |
| p value | 0.87 | 0.44 | 0.216 | 0.03 a | 0.76 | 0.12 | 0.54 | 0.10 | ||
| SS | R | −0.04 | 0.22 | −0.240 | −0.07 | 0.50 | 0.12 | −0.24 | 0.558 | |
| p value | 0.77 | 0.18 | 0.158 | 0.73 | 0.03 a | 0.57 | 0.30 | 0.005 a | ||
| RA | R | 0.06 | 0.78 | −0.370 | −0.13 | −0.13 | 0.30 | −0.38 | −0.08 | |
| p value | 0.68 | 0.64 | 0.022 a | 0.61 | 0.52 | 0.12 | 0.08 | 0.70 | ||
| SLE | R | −0.07 | −0.25 | 0.202 | −0.76 | 0.01 | 0.06 | 0.07 | 0.21 | |
| p value | 0.67 | 0.13 | 0.230 | 0.001 | 0.95 | 0.80 | 0.78 | 0.35 | ||
Abbreviations: ACTDs, autoimmune connective tissue diseases; CRP, C‐reactive protein; CSI, central sensitization inventory; CSI‐A, the first part of central sensitization inventory; CSI‐B, the second part of central sensitization inventory; ESR, erythrocyte sedimentation rate; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SS, Sjögren's syndrome; TSH, thyroid‐stimulating hormone.
Note: Bold values indicate statistical significance at p < 0.05.
Spearman's correlation coefficient.
The comparison of the demographic and clinical features, comorbidity, pain intensity, disease activities, organ involvement, medications, and laboratory findings of patients with ACTDs with CSI‐A score < 40 and CSI‐A score ≥ 40 is shown in Table 5. The CSI‐A score ≥ 40 subgroup had more female gender (n = 44 (95.7) vs. 49 (75.4), p = 0.003), frequency of COPD or asthma (8 (17.4) vs. 0 (0), p = 0.001), more coexisting fibromyalgia (10 (21.7) vs. 8 (12.3), p = 0.014), higher VAS score (5.7 (2.2–10) vs. 4.15 (2.77), p < 0.001), more common exocrine gland involvement (16 (34.8) vs. 11 (16.9), p = 0.026) and a higher CS dose (4 (2–4) vs. 4 (4, 5), p = 0.008) compared to the CSI‐A score < 40 subgroup.
TABLE 5.
The comparison of the demographic and clinical features, comorbidity, pain intensity, disease activities, organ involvement, medications, and laboratory findings of patients with ACTDs with CSI‐A score < 40 and CSI‐A score ≥ 40.
| CSI‐A score < 40 (n = 65) | CSI‐A score ≥ 40 (n = 46) | p a/b | |
|---|---|---|---|
| Age (year), mean (SD) | 48.3 (9.1) | 48.5 (13.5) | 0.927 |
| Female, n (%) | 49 (75.4) | 44 (95.7) | 0.003 |
| BMI (kg/m2), mean (SD) | 27.1 (4.9) | 28.3 (6.0) | 0.198 |
| Disease duration (year), median (IQR) | 7 (2–14) | 2 (2–7) | 0.530 |
| Regular exercises, n (%) | 14 (21.5) | 13 (28.3) | 0.416 |
| History of smoking (pack‐year), median (IQR) | 12.5 (5–20) | 6.5 (3.5–27.5) | 0.241 |
| Comorbidity, n (%) | |||
| Diabetes mellitus | 9 (13.8) | 2 (4.3) | 0.167 |
| Hypertension | 13 (20) | 12 (26.1) | 0.205 |
| Coronary artery disease | 4 (6.2) | 5 (10.9) | 0.132 |
| Thyroid disorder | 11 (16.9) | 11 (23.9) | 0.132 |
| Malignancy | 3 (4.6) | 1 (2.2) | 1.000 |
| Chronic renal failure | 3 (4.6) | 2 (4.3) | 1.000 |
| COPD | 0 (0) | 8 (17.4) | 0.001 |
| Osteoporosis | 2 (3.1) | 3 (6.5) | 0.159 |
| Depression | 0 (0) | 2 (4.3) | 0.091 |
| Disc herniation | 1 (1.5) | 0 (0) | 1.000 |
| Coexisting fibromyalgia, n (%) | 8 (12.3) | 10 (21.7) | 0.014 |
| VAS (cm), mean (SD) | 4.15 (2.77) | 5.7 (2.2–10) | < 0.001 |
| ESSDAI, median (IQR) | 2 (0–2) | 2 (0–4) | 0.496 |
| DAS28 CRP, median (IQR) | 3.2 (2.8–3.5) | 3.57 (3.17–4.2) | 0.090 |
| SLEDAI, median (IQR) | 4 (2–6) | 6 (4–20) | 0.120 |
| Organ involvement, n (%) | |||
| Joint | 56 (86.2) | 41 (89.1) | 0.642 |
| Skin | 13 (20) | 9 (19.6) | 0.955 |
| Lung | 7 (10.8) | 5 (10.9) | 1.000 |
| Cardiac | 4 (6.2) | 1 (2.2) | 0.401 |
| Renal | 13 (20) | 5 (10.9) | 0.199 |
| Central nervous system | 3 (4.6) | 0 (0) | 0.265 |
| Exocrine gland | 11 (16.9) | 16 (34.8) | 0.026 |
| Medications, n (%) | |||
| Methotrexate | 16 (24.6) | 7 (15.2) | 0.229a |
| Leflunomide | 5 (7.7) | 4 (8.7) | 1.000 |
| Hydroxychloroquine | 42 (64.6) | 35 (76.1) | 0.196 |
| Sulfasalazine | 3 (4.6) | 1 (2.2) | 0.641 |
| Colchicine | 4 (6.2) | 4 (8.7) | 0.716 |
| Corticosteroid | 37 (56.9) | 24 (52.2) | 0.620 |
| Corticosteroid dose (mg), median (IQR) | 4 (2–4) | 4 (4–5) | 0.008 |
| Biological DMARD | 11 (16.9) | 4 (8.7) | 0.212 |
| Anti‐TNF | 4 (6.2) | 3 (6.5) | 1.000 |
| Regular NSAIDs | 4 (6.2) | 2 (4.3) | 1.000 |
| Laboratory findings, median (IQR) | |||
| ESR (mm/h) | 19 (6–29) | 17.5 (7–25) | 0.928 |
| CRP (mg/L) | 3 (2–10) | 2.5 (1–7.5) | 0.094 |
| Hemoglobin (g/dL) | 12.8 (12–14) | 12.9 (12–14.5) | 0.774 |
| Vitamin D (nmol/L) | 30.5 (21–65) | 47 (19–62) | 0.550 |
| Folic acid (ng/mL) | 9 (6–12) | 11 (9.4–13) | 0.290 |
| Vitamin B12 (ng/L) | 332 (261–427) | 345 (277–451) | 0.204b |
| Ferritin (μg/L) | 28.5 (19.5–69) | 25 (12–53) | 0.518 |
| TSH (mIU/L) | 1.88 (1.16–3.35) | 1.46 (0.7–2.2) | 0.239 |
Abbreviations: COPD, chronic obstructive pulmonary disease; CRP, C‐reactive protein; CSI, central sensitization inventory; CSI‐A, the first part of central sensitization inventory; DAS‐28 CRP, disease activity score with 28‐joint count and C‐reactive protein; ESR, erythrocyte sedimentation rate; ESSDAI, EULAR Sjögren's Syndrome Disease Activity Index; IQR, interquartile range; NSAIDs, non‐steroidal anti‐inflammatory drugs; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index; TSH, thyroid‐stimulating hormone; VAS, Visual Analog Scale.
Note: Bold values indicate statistical significance at p < 0.05.
χ 2 test or Fisher exact test.
One‐way analysis of variance or Kruskal–Wallis test.
4. Discussion
To the best of our knowledge, the present study is the first to comprehensively evaluate CS in patients with ACTDs and its association with disease activity, laboratory findings, medications, organ involvement, and comorbidity. The study showed that patients with ACTDs had higher CSI scores and were more frequent compared to the healthy population, and patients with SS in particular were evident. The CS was not associated with disease activity in patients with ACTDs (except for patients with RA), but the CS is associated with vitamin D3, folic acid, and TSH in ACTD subgroups. The subgroup with CSI score ≥ 40 had more female gender, a higher prevalence of COPD or asthma, more coexisting fibromyalgia, higher pain score, more prevalent exocrine gland involvement, and a higher CS dose compared to the subgroup with CSI score < 40.
CS is common in many rheumatic diseases such as fibromyalgia, osteoarthritis, axial spondyloarthritis (axSpA), and Behçet's syndrome (BS) [16, 23, 25, 26]. Previous studies in which the prevalence of CS for SpA was reported ranged from 45% to 57.4.% [16, 23, 26, 27, 28] A study showed that clinical CS occurs in 69.3% of patients with BS and is more frequent and severe in patients with BS than in healthy individuals [25]. Another study reported that CS rates were 45.1% for axSpA and that the frequency of severe forms of CS was higher in patients with axSpA than in healthy individuals [26]. A study related to patients with inflammatory arthritis found that the prevalence of CS was 35% in the overall population, 29% in RA, and 42.9% in psoriatic arthritis (PsA) [29]. In a study of different rheumatic diseases, CS syndromes were present in almost half the patients: 45% of SpA, 41% of RA, 62% of OA, and 94% of fibromyalgia patients [23]. In primary SS, the CS rate was detected to be 74%, while the rate was 25.6% in healthy controls [30]. In the current study, ACTDs patients exhibited higher CS scores and CS positivity than the healthy population. The present study detected clinical CS in 41.4% of patients with ACTDs, which is consistent with the literature. Also, the current study found that SS patients had the highest CS positivity (58.3%) among ACTDs, which is consistent with Ökmen et al.'s study rate [30]. A similar prevalence was found in RA patients (36.8%), consistent with the rates of previous studies [23, 29]. To our knowledge, we have not found any studies related to CS in SLE patients. Compared to the healthy population, 29.7% of SLE patients were detected to have CS positivity. The current study showed that, in terms of CSI‐related syndromes, significant among‐groups differences in the prevalence of fibromyalgia were evident. The prevalence of fibromyalgia was highest in the SS group (30.6%). It is possible that the high score and prevalence of CS in SS patients are related to the coexisting fibromyalgia.
A study reported that CS adversely affects disease activity in axSpA patients [26]. Another study confirmed that worse disease activity, more entheseal involvement, and anxiety independently predict the development of CS in axSpA [28]. Ayar et al. [25] showed that there was a positive correlation between CS and BS disease activity. Unlike these studies, Guler, Celik and Ayhan [23] did not find a relationship between CSI score and disease activity in patients with RA and SpA. Adami et al. [29] showed that CSI score was strongly associated with disease activity in PsA, while CSI score was slightly weaker correlated with SDAI in the RA group. Klooster, Graaf and Vonkeman [31] reported that patients with a non‐nociceptive pain phenotype which had more often been diagnosed with concurrent fibromyalgia showed higher disease activity scores. The current study found that there was a low correlation between DAS‐28 CRP and the CSI‐A scores in patients with RA, consistent with Adami et al. and Klooster, Graaf and Vonkeman [29, 31], while there was no relationship between CS and disease activity (ESSDAI, SLEDAI‐2K) in ACTDs subgroups. Also, our results are consistent with findings from previous studies in RA [31, 32]. However, in RA, there are more objective markers that reflect disease activity, such as CRP, swollen joint count by the physician, and joint inflammation. This makes it easier to determine whether chronic widespread pain may still be a result of active disease or is related to nociceptive pain mechanisms in the presence of objective signs of inflammation. Due to the limited study of SS‐ and SLE‐related CS, more studies are needed to clarify the relationship. We think that, with the increasing use of medication with strong anti‐inflammatory and immunosuppressive effects in ACTDs in recent years, inflammation has become more manageable. These treatments may have similar effects on CS, and this issue needs to be investigated.
A review related to autoimmune rheumatic diseases and vitamin D3 found that Vitamin D3 deficiency has been found in patients with RA, SLE, SS, and axSpA and has been linked to disease activity. Also, in the review, in SLE, vitamin D3 was found to be inversely associated with disease activity and renal involvement. The review suggests that vitamin D3 deficiency may play a role in the pathogenesis of autoimmunity, and therefore, vitamin D3 may be used to prevent autoimmune disease and relieve pain in autoimmune rheumatic diseases [33]. A review showed that vitamin D3 has been inversely correlated with painful manifestations, such as fibromyalgia and rheumatic diseases [34]. Consistent with previous studies, the current study found that CSI scores were inversely correlated with vitamin D3 in patients with SLE. Also, CSI‐B scores were very low correlated with vitamin D3 in patients with ACTDs. With vitamin D3 deficiency, concomitant CS‐related symptoms are also seen to increase. Consistent with Athanassiou et al.'s finding [33], renal involvement was particularly common in SLE (approximately half of the patients; 48.6%) in the current study. These results may also be related to the extent of renal involvement. Future studies need to comprehensively investigate the relationship between CS and vitamin D3 in rheumatoid diseases. In addition, in these patients, vitamin D3 deficiency should be carefully evaluated. The literature on CS and laboratory findings in rheumatic diseases is limited. To the best of our knowledge, the present study is the first comprehensive study of these diseases.
Bell et al. [35] found that folate and vitamin B12 are essential for the regulation of the CNS and that their deficiency results in peripheral neuropathy pain. The positive effects of B12/folic acid supplementation on fibromyalgia patients have been reported [36]. In particular, if the thyroid gland does not produce sufficient levels of hormones, symptoms such as muscle pain and spasms, weight gain, depression, and fatigue may begin to occur [37]. Overall, these findings strongly show a link between chronic pain and thyroid function [37]. Indeed, depressed patients have lower basal serum TSH levels (albeit within the normal range), according to study [38]. In general, thyroid patients can suffer musculoskeletal symptoms, and there is a relationship between thyroid autoimmunity and the presence of fibromyalgia [39]. Indeed, thyroid hormone disorders have been linked to arthritis, arthralgia, myopathies, and fibromyalgia. In particular, chronic musculoskeletal pain was found to be less common in women with high TSH than in those with normal or low values [40]. The current study showed that CSI‐B score was moderately correlated with folic acid and TSH in SS patients. Also, unlike the subgroups of ACTDs, the present study found a higher prevalence of fibromyalgia in SS patients (30.6%). Consistent with Bazzichi et al.'s [39] study results, it is possible to say TSH (albeit within the normal range) may induce chronic musculoskeletal pain and fibromyalgia, causing CS symptoms. Also, folic acid deficiency may increase musculoskeletal pain, consistent with previous studies [36, 41]. Especially in SS patients who complain of CS symptoms, laboratory findings such as TSH and folic acid should be well monitored, and CS can be treated with necessary supplements.
A cross‐sectional study showed that female patients scored significantly higher on patient‐reported measures of disease activity, whereas objective measures of disease activity (CRP and swollen joints) were comparable between the genders [42]. A review showed that chronic pain associated with RA typically occurs in patients with anxiety, female sex, and elevated inflammatory status [43]. A review reported that, in AxSpA cohorts, the prevalence has been reported at 4%–25%, and in PsA at 16%–22%, with the majority being female [44]. A study suggested that patients with RA and SLE should be evaluated for fibromyalgia since 20%–30% of them have associated fibromyalgia, requiring a different treatment approach [45]. Consistent with previous studies, we found that the CSI score ≥ 40 subgroup had more females and coexisting fibromyalgia. Interestingly, in the present study, the presence of COPD was found to be higher in the group with a CSI above 40. A recent study reported that high fibromyalgia is associated with persistent glucocorticoid use, independent of inflammatory activity, in patients with RA [46]. In another study, no difference was found in terms of the prevalence of CS in PsA patients using and not using steroids [29]. The current study showed that the CSI score ≥ 40 subgroup had a higher CS dose consistent with Wallace et al.'s study [46]. Also, the CSI score ≥ 40 subgroup had more common exocrine gland involvement. In particular, in SS patients in whom exocrine gland involvement is common, this result may be related to the more common prevalence of fibromyalgia and CS.
The study has some limitations. These results are not easily generalizable to all patients with ACTDs, which cover a broad spectrum. First, patients' psychological states were not evaluated in this study, but CS may be affected by psychological factors. Second, we did not evaluate neuropathic pain profiles in ACTD patients. Unfortunately, up until now, no laboratory findings have been available to assess in studies related to CS in rheumatic disease. An important strength of our study is its comprehensiveness in evaluating the potential contributors (disease activity, pain intensity, laboratory findings, medications, organ involvement, and comorbidity) of CS in patients with ACTDs.
In conclusion, CS is seen as a common condition in patients with ACTDs, especially in SS patients. The CS is associated with vitamin D3, folic acid, and TSH levels in ACTD subgroups. The profile of patients with clinical CS is that they are female, have a higher prevalence of COPD, coexist with fibromyalgia, have a higher pain score, have more prevalent exocrine gland involvement, and have a higher CS dose. A multimodal biopsychosocial perspective should be considered for ACTDs with chronic musculoskeletal pain in the early stages. It is essential to increase awareness about the important role played by CS pain in patients with ACTDs.
Author Contributions
Zilan Bazancir‐Apaydin: conceptualization; methodology; formal analysis; investigation; writing – original draft preparation. Hakan Apaydin: methodology; investigation; writing – original draft preparation; resources. Berkan Armagan: conceptualization; methodology; investigation. Kevser Orhan: methodology; investigation; supervision. Sukran Erten: conceptualization; writing – review and editing; supervision.
Ethics Statement
This study was approved by the Ankara City Hospital Clinical Researches Ethics Board (ID. E2‐22‐1510, 04/13/2022).
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgments
The authors have nothing to report.
Funding: The authors received no specific funding for this work.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.