This cross-sectional, case-control study assesses the prevalence of central sensitization in patients with hidradenitis suppurativa compared with sex- and age-matched controls in the Netherlands.
Key Points
Question
What is the prevalence of central sensitization (altered and amplified pain perception) in patients with hidradenitis suppurativa (HS)?
Findings
This cross-sectional, case-control study of 100 patients with HS and 100 controls in the Netherlands showed a significant difference in the prevalence of a Central Sensitization Inventory score of 40 or higher, indicative of central sensitization. Patients with HS were found to have 4.46 times the odds of having a positive Central Sensitization Inventory score.
Meaning
The increased odds for central sensitization among patients with HS raises the question of whether we are adequately measuring and treating HS-associated pain.
Abstract
Importance
Chronic pain is one of the most prominent symptoms of hidradenitis suppurativa (HS) and an independent domain in the core outcome set for HS. Previously, the chronic, recurrent, inflammatory nature of HS was hypothesized to induce central sensitization (CS; alteration and amplification of pain perception). However, evidence for this hypothesis is currently lacking.
Objective
To determine the prevalence of CS in patients with HS compared with sex- and age-matched controls.
Design, Setting, and Participants
This was a cross-sectional, survey-based, case-control study conducted from February to November 2020 that included all consecutive adult patients with HS attending the outpatient clinic of the Department of Dermatology of the Erasmus University Medical Center Rotterdam, in Rotterdam, the Netherlands. Age- and sex-matched controls without chronic inflammatory dermatologic diseases were recruited from the same department.
Main Outcomes and Measures
The main outcome was the Central Sensitization Inventory (CSI) score (ranging from 0-100) as a screening tool for presence of CS. Based on current literature, a score of 40 or higher was deemed to indicate the presence of CS.
Results
Overall, 100 patients with HS (median [IQR] age, 34.5 [27.3-47.0] years; 71 [71%] female) and 100 controls (median [IQR] age, 33.5 [27.0-48.8] years; 71 [71%] female) were included, of which 36% and 12%, respectively, had a CSI score of 40 or higher (P < .001). Multivariate logistic regression showed that patients with HS had 4.46 (95% CI, 1.89-10.52; P = .001) times the odds of having a positive CSI compared with controls. In addition, CS was significantly associated with previously diagnosed depression (odds ratio, 6.16; 95% CI, 2.81-13.54; P < .001). No association between CSI score and disease severity was found.
Conclusions and Relevance
In this cross-sectional, case-control study, patients with HS had more than 4 times the odds of having CS, indicated by a positive CSI, compared with age- and sex-matched controls. This new insight in the presence of CS in patients with HS raises the question of whether we are adequately measuring and treating HS-associated pain. Active screening for CS and depressive symptoms in patients with a discrepant pain experience is recommended.
Introduction
Pain is one of the most prominent and debilitating symptoms of hidradenitis suppurativa (HS) and has been incorporated as a domain in the newly developed core outcome set for HS.1 The chronic, inflammatory, and painful nature of HS has been postulated to induce a process known as central sensitization (CS).2 Central sensitization is an increased responsiveness of the pain perception pathway in the central nervous system to normal or subthreshold stimuli, altering and amplifying pain perception.2 Symptoms of CS are not confined to pain and can include fatigue, memory loss, and sleep disturbances.2 Moreover, several syndromes have been associated with CS. For example, fibromyalgia and irritable bowel syndrome are considered to share a common pathophysiological pathway, implicating neuronal hyperexcitability as the central mechanism.2
The presence of CS in HS-associated inflammatory diseases, such as inflammatory bowel disease and rheumatic diseases, has been well established.3,4 Therefore, the aim of this study was to assess the prevalence of central sensitization in patients with HS compared with age- and sex-matched controls.
Methods
Study Design
This cross-sectional, survey-based, case-control study was performed at the Department of Dermatology of the Erasmus University Medical Center Rotterdam, in Rotterdam, the Netherlands, from February to November 2020. All consecutive, adult patients with HS were included during routine clinic visits. Patient characteristics, comorbidities, skin-related pain, and disease severity scores were collected. Age-matched (within 3 years) and sex-matched controls were recruited during routine care from the same population as the patients with HS—namely, the dermatology outpatient clinic of the Erasmus University Medical Center—and patient characteristics were collected. Exclusion criteria for controls were presence of HS, or other chronic, inflammatory dermatological diseases in more than 1 body area (eg, psoriasis, atopic dermatitis, or acne conglobata). The ethical committee of the Erasmus University Medical Center Rotterdam verified that the Medical Research Involving Human Subjects Act (WMO) did not apply to this research (MEC-2020-0030) and waived the need for review and patient informed consent. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
Central Sensitization Inventory
The first part of the CSI assesses 25 health-related symptoms common to CS, scored from 0 (never) to 4 (always), with the total score ranging from 0 to 100.5,6 Using a cutoff value 40 or higher as indication for the presence of CS has shown good test-retest validity with a sensitivity and specificity of 81% and 75%, respectively.5 The Dutch version of the CSI was validated with an intraclass correlation coefficient of 0.88 for patients with chronic pain and 0.91 for controls.6 The second part assesses the previous diagnosis of 10 CS-associated conditions.
Statistical Analysis
A power calculation showed that 100 participants per group would result in a power of 80% to detect a CSI difference (SD) of 6 (15) points. Between-group comparisons were performed using unpaired t tests or Mann-Whitney U tests and χ2 tests or Fisher exact tests where appropriate. Variables associated with CS (eMethods in the Supplement) were tested in univariate and multivariate regression models (dichotomous CSI score: <40, ≥40). All comparisons were 2-sided, and P ≤ .05 was considered statistically significant. Statistical analyses were performed using SPSS Statistics, version 26.0 (IBM Corporation).
Results
A total of 100 patients with HS (median [IQR] age, 34.5 [27.3-47.0] years; 71 [71%] female) and 100 age- and sex-matched controls (median [IQR] age, 33.5 [27.0-48.8] years; 71 [71%] female) were included. Differences between patients with HS and controls and the most common dermatologic diagnoses of the control patients are listed in Table 1.
Table 1. Patient Characteristics.
| Characteristic | No. (%) | P value | |
|---|---|---|---|
| Patients with HS | Controls | ||
| No. | 100 | 100 | NA |
| Age, median (IQR) | 34.5 (27.3-47.0) | 33.5 (27.0-48.8) | NS |
| Sex | |||
| Female | 71 (71) | 71 (71) | NS |
| Male | 29 (29) | 29 (29) | |
| Age at onset, median (IQR), y | 18 (15.0-24.8) | NA | NA |
| Family history | 32 (32) | NA | NA |
| BMI, median (IQR) | 28.9 (24.7-33.3) | 23.4 (21.7-26.8) | <.001 |
| Current or former smoker | 69 (69) | 22 (22) | <.001 |
| History | |||
| IBD | 8 (8) | 0 | .007 |
| Rheumatic disease | 4 (4) | 2 (2) | NS |
| Diabetes mellitus | 7 (7) | 0 | .01 |
| Hurley stage | |||
| I | 64 (64) | NA | NA |
| II | 34 (34) | NA | NA |
| III | 2 (2) | NA | NA |
| IHS4 score, median (IQR) | 0 (0-4) | NA | NA |
| Mild | 74 (74) | NA | NA |
| Moderate | 18 (18) | NA | NA |
| Severe | 8 (8) | NA | NA |
| AN count, median (IQR) | 0 (0-1.8) | NA | NA |
| NRS pain score, median (IQR) | 3 (0-3) | NA | NA |
| Current analgesic medication | |||
| Nonopioid medication | 4 (4) | NA | NA |
| Opioids | 1 (1) | NA | NA |
| Central sensitization (part A CSI) | |||
| CSI score | |||
| Median (IQR) | 31 (19.0-44.8) | 25 (16.0-34.0) | .002 |
| Mean (SD) | 33.7 (18.7) | 25.1 (12.0) | .003 |
| CSI score ≥ 40 | 36 (36) | 12 (12) | <.001 |
| CSS diagnoses (part B CSI) | |||
| 0 | 45 (45) | 57 (57) | .046 |
| 1 | 27 (27) | 29 (29) | |
| >1 | 28 (28) | 14 (14) | |
| Depression | 27 (27) | 19 (19) | .24 |
| Dermatologic diagnosis | |||
| Benign lesiona | NA | 40 (40) | NA |
| Skin cancerb | NA | 27 (27) | NA |
| Mild acne vulgaris | NA | 17 (17) | NA |
| Other | NA | 16 (16) | NA |
Abbreviations: AN, abscess and nodule; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); IBD, inflammatory bowel disease; CSI, Central Sensitization Inventory; CSS, central sensitization syndrome; HS, hidradenitis suppurativa; IHS4, International Hidradenitis Suppurativa Severity Score System; IQR, interquartile range; NA, not applicable; NRS, numeric rating scale; NS, not significant.
Including melasma, verrucae, keloid, and naevus naevocellularis.
Including basal cell carcinoma and squamous cell carcinoma.
Patients with HS had a significantly higher median (IQR) CSI score (31 [19.0-44.75]) than controls (25 [16.0-34.0]) (P = .002). Thirty-six percent of patients with HS had a positive CSI with a score of 40 or higher vs 12% of control patients (P < .001).
Univariate logistic regression of all 200 participants identified a significantly increased odds ratio for a positive CSI among patients with HS (4.13; 95% CI, 1.99-8.55; P < .001), current or former smokers (2.22; 95% CI, 1.14-4.30; P < .05) and participants with previously diagnosed depression (5.91; 95% CI, 2.87-12.19; P < .001). Multivariate logistic regression analysis identified patients with HS as having 4.46 (95% CI, 1.89-10.52; P = .001) times the odds of having a positive CSI compared with age- and sex-matched controls (Table 2). No significant association was found between Hurley stage, International Hidradenitis Suppurativa Severity Score System (IHS4) score, or abscess and nodule count and CS within the HS group (eMethods in the Supplement).
Table 2. Univariate and Multivariate Regression Analyses (n = 200).
| Characteristic | Regression | |||
|---|---|---|---|---|
| Univariate | Multivariate | |||
| OR (95% CI) | P value | OR (95% CI) | P value | |
| Hidradenitis suppurativa | 4.13 (1.99-8.55) | <.001 | 4.46 (1.89-10.52) | .001 |
| Depression | 5.91 (2.87-12.19) | <.001 | 6.16 (2.81-13.54) | <.001 |
| Smoking | 2.22 (1.14-4.30) | .02 | 0.87 (0.38-1.96) | .73 |
| Diabetes mellitus | 0.52 (0.06-4.41) | .55 | NA | NA |
| BMI | 1.01 (0.95-1.07) | .72 | NA | NA |
| Female | 1.75 (0.81-3.81) | .16 | NA | NA |
| Age | 0.98 (0.96-1.01) | .20 | NA | NA |
| Other inflammatory diseasea | 2.09 (0.65-6.73) | .22 | NA | NA |
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); NA, not applicable; OR, odds ratio.
Inflammatory bowel disease and rheumatic comorbidities.
Previous physician diagnoses of CS-associated syndromes identified through the second part of the CSI were significantly more common among patients with HS than controls (55% vs 43%; P < .05) (Table 3). Patients with HS were significantly more likely to have more than 1 of these CS diagnoses than controls (28% vs 14%; P < .05).
Table 3. Central Sensitization Diagnoses Reported in the Central Sensitization Inventory.
| Diagnosis | No. (%) | |
|---|---|---|
| Patients with HS (n = 100) | Controls (n = 100) | |
| Restless legs syndrome | 3 (3) | 2 (2) |
| Chronic fatigue syndrome | 5 (5) | 1 (1) |
| Fibromyalgia | 6 (6) | 2 (2) |
| Temporomandibular joint disorder | 5 (5) | 2 (2) |
| Tension headache/migraine | 17 (17) | 15 (15) |
| Irritable bowel syndrome | 10 (10) | 3 (3) |
| Multiple chemical sensitivities | 7 (7) | 4 (4) |
| Neck injury | 3 (3) | 5 (5) |
| Anxiety/panic attacks | 20 (20) | 13 (13) |
| Depression | 27 (27) | 19 (19) |
Abbreviation: HS, hidradenitis suppurativa.
Discussion
To our knowledge, this is the first study investigating the presence of CS, as determined by a CSI score of 40 or higher, and associated conditions in patients with HS compared with age- and sex-matched controls. The mean (SD) CSI score found in patients with HS (33.7 [18.7]) is in line with previously reported CSI scores in inflammatory bowel disease, spondyloarthritis, and rheumatoid arthritis: 26.23 (12.68), 36.26 (18.51), and 38.43 (16.2), respectively.3,4 These inflammatory diseases share a frequently seen pattern in which pain symptoms cannot always be linked to underlying inflammation or peripheral mechanisms. The current study identifies CS as a potential explanation for the discrepancy between high reports of clinical entheseal pain symptoms without underlying sonographic findings as seen in a previous HS study.2 The high prevalence of CS in patients with HS highlights potential difficulties in measuring pain in this population. Pain reported by patients with CS could be less responsive to treatment and clinical trials might show little improvement on pain scores, despite the efficacy of the treatment. Therefore, screening for CS prior to study initiation could be essential to elucidate any discrepancies in the reduction of pain scores and clinical disease severity scores.
Depression is a common comorbidity among patients with HS and has a significant and well-documented association with chronic pain.7,8 Our analysis showed a strong independent association of depression with CS. Even though both pain and depression have been well-studied among patients with HS, their interaction is rarely discussed.9,10 Accepting that the two have a mutually reinforcing role means that pain should not be measured without assessing depression.
Limitations
A limitation of this study is that the CSI has not yet been validated in HS. However, it has been validated in chronic pain including dermatologic symptoms.6 Another limitation could be the selection of the control population, as this included patients with other dermatologic diseases rather than healthy controls. However, the controls were randomly selected from the same dermatology outpatient clinic as the patients with HS, making them a representative sample of the population that produced the cases.
The majority of included patients with HS have mild disease severity, which has potentially influenced the lack of an association between CSI and disease severity scores. However, this mild population already shows a remarkably increased CSI score compared with controls. A final limitation is the wide ranges of the CSI scores. This is most likely a result of the variance within the population rather than the sample size, as this is comparable to other studies using the CSI.4,11,12
Conclusions
In this cross-sectional, survey-based, case-control study, patients with HS were found to have more than 4 times the odds of having CS, indicated by a positive CSI, compared with age- and sex-matched controls. This raises the question of whether we are adequately measuring and treating HS-associated pain. We recommend active screening for both CS and depressive symptoms in patients with a discrepant pain experience.
eMethods.
References
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Associated Data
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Supplementary Materials
eMethods.