Introduction
Ankylosing spondylitis (AS) is a chronic, progressive inflammatory disease that classically affects the axial skeleton, especially vertebrae and sacroiliac joints.Reference Taurog, Chhabra and Colbert1 Extra-articular manifestations vary in terms of frequency and severity.Reference Stolwijk, Van Tubergen, Castillo-Ortiz and Boonen2 The most common extra-articular manifestations are represented by uveitis, bowel disease, heart, lung, skin, bone, and kidney involvement.Reference El Maghraoui3 Overall, the prevalence of AS is around 1%,Reference Exarchou, Lindström and Askling4 and its incidence is around 20 per 10,000 people per year in studies from different countries.Reference Wang and Ward5
Neurological impairment is not usually observed in AS. However, it is increasingly recognized that autoimmune rheumatological diseases can be accompanied by cognitive dysfunction, with demographic factors, medical comorbidities, and medical treatment acting as potential risk factors.Reference Simos, Ktistaki and Dimitraki6,Reference Vitturi, Nascimento, Alves, de Campos and Torigoe7 One hypothesis for dementia in AS is the neurodegeneration caused by systemic inflammation.Reference Chen, Chen and Fan8 Long-term or high-dose treatments with anti-inflammatory drugs are commonly used in rheumatic diseases and may decrease the volume of the hippocampus, causing cognitive impairment as well.Reference Ramos-Remus, Duran-Barragan and Castillo-Ortiz9 Neuropsychiatric involvement has been suggested to be important in AS patients as well.Reference Martindale, Smith, Sutton, Grennan, Goodacre and Goodacre10 Besides, recent experimental studies found altered regional activity and neural networks between the brains of patients with AS and healthy controls.Reference Li, Wei and Zou11
Little is known about the potential systemic effects of AS on the nervous system. Nevertheless, cognitive manifestations might be underestimated or even unknown in AS. In parallel, in 2012, the World Health Organization announced that dementia is one of the highest priority public health issues globally.Reference Wortmann12 This study aimed to assess the frequency and clinical predictors of cognitive impairment in AS patients.
Methods
Study Design and Subjects
We carried out a cross-sectional case–control study composed of consecutive patients with AS who were under regular clinical follow-up in the Rheumatology Unit of a university-affiliated, tertiary referral hospital between January 2016 and December 2018. Patients were considered eligible for the study if they aged 18 years or older and had been diagnosed with AS. The diagnosis of AS was made based on the American College of Rheumatology diagnostic criteria.Reference Ward, Deodhar and Akl13 Patients diagnosed with dementia before AS were excluded from this study. Participants completed questionnaires and cognitive testing on the day of enrollment. Volunteers from the control group were randomly selected from the healthy patient population enrolled in our hospital. No patient with any previous rheumatologic or neurological disease was included. Information regarding patients with AS were ranked in order to recruit the individual from the control group. It was matched at a 1:1 ratio according to a propensity score that considered age, sex, comorbidities, and level of education. Examiners who applied the cognitive tests with controls were blinded to data from patients with AS. All participants provided written informed consent before inclusion, and the research protocol was approved by our local ethics committee.
Baseline Measures and Comorbidities
Trained interviewers conducted structured and standardized in-person assessment interviews with questionnaires that captured socio-demographic and clinical characteristics including sex, date of birth, total years of formal education, comorbidities (e.g. hypertension, diabetes, hyperlipidemia, and smoking status), and use of medications. The previous diagnosis of a neurological or psychiatric disorder was also investigated. We obtained information on disease’s characteristics such as disease duration, disease-related symptoms, and use of oral glucocorticoids, disease-modifying antirheumatic drugs and tumor necrosis factor inhibiting biological therapy. Disease activity was assessed using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)Reference Garrett, Jenkinson, Kennedy, Whitelock, Gaisford and Calin14 and The Ankylosing Spondylitis Disease Activity Score (ASDAS-CRP/ASDAS-ESR).Reference Lukas, Landewé and Sieper15 BASDAI measures the severity of fatigue, spinal and peripheral joint pain, localized tenderness, and morning stiffness (both qualitative and quantitative). Additionally, ASDAS considers the values of CRP and ESR. Both scores are well validated in clinical practice, and they show good discriminative ability and high discriminatory assessment of AS disease activity. Functional limitations were assessed using the Health Assessment Questionnaire (HAQ), one of the most widely used measures of functioning in RA research. The HAQ includes 20 items covering physical actions in 8 domains: dressing and grooming, arising, eating, walking, personal hygiene, reaching, gripping, and outdoor activities. HAQ scores range from 0 to 3 with higher scores reflecting greater functional limitations.Reference Bruce and Fries16
Outcomes
Neurological status was assessed by structured face-to-face tests performed by experienced physicians blinded to each subject’s clinical status. The severity of current symptoms of depression and anxiety was determined via the Hospital Anxiety and Depression Scale (HADS), a 14-item questionnaire that assesses symptoms of depression (HADS-D) and anxiety (HADS-A). Total scores range from 0 to 21 on each scale.Reference Zigmond and Snaith17 The HADS has already been validated for use in AS and the general population.Reference Zhao, Thong and Miller18 While scores ≥ 11 indicated probable anxiety or depression, the specificity of the HADS-A and HADS-D is high (>90%) in AS at this threshold.
The cognitive assessment included Brief Cognitive Screening Battery (BCSB)Reference Fichman-Charchat, Miranda and Fernandes19 and the Montreal Cognitive Assessment (MoCA).Reference Nasreddine, Phillips and Bédirian20 BCSB and MoCA are useful screening tools for global cognition that have already demonstrated its validity for detecting cognitive impairment and dementia. Both scores were translated and adapted for use in Brazil, and they presented good internal consistency, test–retest reliability, and content validity. Using the conventional validated cut points, subjects were classified as “impaired” or “unimpaired”. The performance of each cognitive domain was registered as well.
The BCSB is a tool for assessing cognitive mental status which can be administered in less than 10 minutes by following simple instructions.Reference Nitrini, Caramelli and Porto21 It evaluates visual perception (0–10 points for identification of 10 figures and 0–10 points for their nomination, where no mistakes are expected in healthy individuals), incidental memory (0–10 points), immediate memory (0–10 points, where < 5 points may indicate attention impairment), verbal fluency (where literate individuals are expected to list > 12 animal names, while illiterate unimpaired individuals are expected to list > 8), clock drawing (0–10 points), late memory (0–10 points, where healthy individuals are expected to score 5 > points), and recognition (0–10 points, where < 9 points is considered abnormal). The MoCA is a 30-point test administered in 10–15 minutes, and through 10 subtests it can evaluate visuospatial/executive skills (0–5 points), naming (0–3 points), attention (0–6 point), language (0–3 points), abstraction (0–2 points), delayed recall (0–5 points), and orientation to time and place (0–6 points). Cognitive impairment was defined by a MoCA score < 26, a cutoff previously validated in the general population. To control for educational status, we added 1 point to the MoCA score in patients with < 12 years of education.Reference Nasreddine, Phillips and Bédirian20
Furthermore, the Clinical Dementia Rating (CDR) test was used to assess cognitive impairment and dementia. CDR is a global rating device that was found to distinguish unambiguously and with good reliability among subjects with a wide range of cognitive functions.Reference Hughes, Berg, Danziger, Coben and Martin22 It has been translated, adapted, and validated for use in Brazil.Reference Beatriz, Monta and Ramos23 CDR evaluates cognition and behavior, as well as the influence of cognitive losses in the subject’s ability to perform adequately daily activities. It is divided into six cognitive-behavioral categories: memory, orientation, judgment or problem solving, community affairs, home and hobbies, and personal care. Each of these categories should be classified in: 0 (no impairment), 0.5 (questionable), 1 (mild dementia), 2 (moderate dementia), or 3 (severe dementia) – except for the category “personal care”, for which the 0.5 level does not exist. Memory is considered the primary category, and all others are secondary. The global CDR is the sum of the scores of the six categories. Dementia was diagnosed according to DSM-IV criteria, with memory impairment defined by scores below the 95% confidence interval of healthy controls’ performance in the delayed recall sections of both the MoCA and the BCSB, in conjunction with altered scores in at least one additional cognitive test and functional impairment.
Statistical Analysis
Categorical variables were analyzed using the chi-square test or Fisher’s exact test, and differences in continuous variables were assessed using the student’s t-test (parametric test) or the Mann–Whitney test (non-parametric test). Confounding variables included age, educational attainment, cardiovascular risk, smoking, alcohol abuse, and other comorbidities. Multivariate logistic regression and linear regression were also used to identify potential predictors of cognitive impairment and included variables that have been linked with cognitive impairment in previous studies. The limit for significance was set at two-tailed p = 0.05. All analyses were conducted using SPSS, version 23.0.
Results
We included 40 patients with AS and 40 healthy controls in our study. Both groups were homogeneous regarding age, educational attainment, sex, and comorbidities. All patients were under regular treatment for AS. No patients received any opioids or neurological drugs for pain management (e.g. antiepileptic drugs). Demographic and clinical characteristics are summarized in Table 1.
Table 1: Demographics and clinical characteristics of AS patients and healthy controls at baseline
Among the BCSB variables, we found significant differences between AS patients and controls in clock drawing and verbal fluency (p < 0.05) (Table 2). The mean MoCA scores were significantly lower in AS subjects compared to the control group (p < 0.05). Detailed analysis of MoCA revealed that there was a statistical difference between cases and controls in almost all cognitive domains, except for nomination, orientation, and delayed recall. In the individual analysis, there were 36 (90.0%) patients classified as cognitively impaired according to MoCA compared to only 23 (57.5%) healthy controls (p = 0.02). One patient (age: 60 years; sex: female) met the diagnostic criteria for dementia. The mean HAD score was significantly higher in AS subjects (p = 0.003). Moreover, compared with controls, patients with AS were more likely to present an impaired HAD score (32.5% vs 10.0%, p = 0.02).
Table 2: Comparison of BCSB variables, MoCA, and HAD scores between AS patients and healthy controls. Data are expressed in means (standard deviation)
The mean CDR was significantly higher in AS patients (1.3 ± 1.0) compared to controls (0.4 ± 0.6) (p < 0.001). The distribution of study participants according to the CDR demonstrates a higher propensity for AS patients to be classified with pronounced cognitive decline (Figure 1). On multivariable logistic regression, there was no statistically significant clinical predictor identified (Table 3). Also, there was no correlation between cognitive impairment and BASDAI and ASDAS scores (Table 4). On the other hand, on linear regression, HAQ was correlated with MoCA (r = −0.42; p = 0.006) and HAD score (r = 0.31; p = 0.05).
Figure 1: Distribution of patients and controls according to CDR values.
Table 3: Multivariate analysis of possible clinical predictors of neurological impairment in patients with AS according to the MoCA and HADS
* Impossible to calculate the OR due to prevalence of 0% or 100%.
Table 4: Comparison of disease characteristics and neurological outcomes on multivariate logistic regression. Data are expressed in mean and standard deviation (SD)
Discussion
We suggest that patients with AS might be vulnerable to cognitive decline and dementia. The only previous similar evidence that refers to a recent nationwide cohort study found that the prevalence of dementia in the AS group was significantly higher than those of the control group.Reference Jang, Park and Kim24 Also, cerebral functional deficits in patients with AS have already been observed in fMRI.Reference Li, Wei and Zou11
There are several possible explanations for cognitive impairment in patients with AS. Over the last decade, the presence of sustained immune response in the brain has emerged as a core pathology in dementia.Reference Kinney, Bemiller, Murtishaw, Leisgang, Salazar and Lamb25 Systemic inflammation during midlife, whose example is exactly AS, was recognized as an early risk factor for cognitive decline.Reference Walker, Gottesman and Wu26 In another study, a subjective cognitive complaint was reported in a quarter of AS patients.Reference Sunkureddi, Gibson, Doogan, Heid, Benosman and Park27 Furthermore, many previous studies demonstrated that patients with autoimmune rheumatic diseases are more likely to develop dementia.Reference Lin, Chen, Sheu, Chen, Chen and Chang28 Currently, there is a growing literature demonstrating the relationship of multimorbidity and dementia as well.Reference Song, Mitnitski and Rockwood29
Another explanation comes from the extracellular deposit of amyloid, which besides being known as one of the abnormalities observed in Alzheimer’s Disease,Reference Wang, Gu, Masters and Wang30 is also implicated in AS patients showing an increased level of serum amyloid.Reference Lange, Boss, Teichmann, Klör and Neeck31 Social and physical activity are severely affected by AS.Reference Prince, Mcguigan and Mcgirr32 Disturbed sleep is a common finding of the disease as well.Reference Leverment, Clarke, Wadeley and Sengupta33 These are all comorbidities known to have a significant effect on cognitive ability.Reference Jedrziewski, Lee and Trojanowski34,Reference Wennberg, Wu, Rosenberg and Spira35 Patients with AS also present an increased cerebrovascular risk,Reference Lee, Choi and Han36 which is a known cause of vascular dementia. Furthermore, common medications used for AS treatment may be involved in the pathogenesis of cognitive impairment. Glucocorticoid therapy has already been associated with an immediate impact on memory and a possible cumulative influence on hippocampal function.Reference Coluccia, Forster, Kollias, de Quervain, Roozendaal and Wolf37 In contrast, other studies suggest the potential benefits of anti-TNF-α therapies to prevent or slow the progression of Alzheimer’s Disease.Reference Decourt, Lahiri and Sabbagh38
Patients with AS were more likely to present neuropsychiatric symptoms. This finding is in line with previous studies that found a risk to mood disorders 2–3 times higher whether AS is diagnosed.Reference Park, Jang and Hong39 Furthermore, neuropsychiatric disorders are commonly related to dementia. The prevalence of depression in dementia has been reported to be between 9 and 68%. Depression has been both proposed to be a risk factor for dementia as well as a prodrome of dementia.Reference Byers and Yaffe40
Functional limitations were associated with worse neurological outcomes in our study. This finding indicates that either intense disease activity or chronic sequelae of AS can explain worse performance on the neurological assessment. Previously, functional limitations have already been linked with cognitive function in rheumatic diseases.Reference Vitturi, Nascimento, Alves, de Campos and Torigoe7 Apart from HAQ, we did not identify any other predictor of cognitive decline, despite evaluating a wide range of variables. This fact may perhaps be better evaluated in longitudinal multicenter studies involving a large number of patients. ASDAS and BASDAI may not be sensitive enough to detect neurological manifestations of the disease and suffer acute/subacute variations according to the evolution and treatment of the disease, limiting its use as a marker for dementia in patients with AS. In addition, current data support that the inflammatory disease activity might be less prominent with aging, when dementia risk increases.
The strengths of this study include that our study cohort was prospectively followed up and details could be acquired by a comprehensive review of their medical records, by telephone interviews and by face-to-face assessments with trained neurologists who were blind to patients’ clinical characteristics and AS severity. Our work is pioneering in demonstrating AS patients’ susceptibility to cognitive decline. Furthermore, this the largest study performed to screen neurological dysfunction in patients with AS. The results of the study are for a matched population, which is a strength of the study as it minimizes potential confounding bias. Moreover, we were able to assess several possible risk factors that could explain cognitive impairment in RA.
The present study has a few limitations. First, because our research is a single-center, hospital-based study, rather than a community-based study, it is unclear to what extent findings can be generalized. Also, possible biases related to our method of patient and controls inclusion are also pertinent. Nevertheless, there are no restrictions to be admitted to our hospital, and we included all consecutive cases admitted. Besides, the single-center design allowed us to collect information systematically and to uniformly verify both the qualifying event as well as follow-up information in all patients, which reduces the risk of information bias. Second, the biases inherent in an observational study are also applicable to our research. Third, this was a cross-sectional study, and therefore, in spite of statistically significant findings regarding the relationship between the variables of interest, the causal pathway to cognitive impairment could not be determined. Fourth, we didn’t use extensive batteries of neuropsychological tests to assess cognitive impairment. Nevertheless, we intended to evaluate the broadest spectrum of cognitive impairment in AS because even mild levels of impairment can disrupt daily functioning. Moreover, brief screening approaches hold value in that they may rapidly identify those at greatest need for services or facilitate large-scale research to study cognitive compromise in rheumatic diseases. In fact, in clinical practice, screening cognitive tests are commonly the first step in detecting cognitive impairment and in establishing the diagnosis of dementia, especially in the initial investigation of a possible newly discovered cause of dementia, like AS. Fifth, the low education of our population may decrease the sensitivity of MoCA. However, in addition to employing an adjustment for low education that has already been validated in other previous studies, we quantitatively compared the results of MoCA and controls and the education factor was included in the multivariate analysis. Anyway, we emphasize the need for future studies to define the best form of neurological investigation of patients with rheumatologic diseases, something that does not exist in the literature today. Finally, there may have been some degree of overlap between the CDR and the HAQ. However, each questionnaire has been developed and extensively validated for specific purposes, so that your questions are much more sensitive to their original purpose. Moreover, in our research, the application of these instruments was done at different times by blinded examiners. However, every test has disadvantages, and there is still no recommendation or specific tool for the cognitive assessment of patients with rheumatic diseases.
Conclusions
Patients with AS are more vulnerable to cognitive decline. Our findings enhance the understanding of the total burden for AS patients and may contribute to improved health assessment and treatment planning. Considering the severity of dementia, finding a high-risk group of vulnerable subjects based on various risk factors is a fundamental task in the prevention of disease in AS patients. Further longitudinal studies dedicated to diagnosing dementia in AS patients are encouraged.
Conflict of Interest
The authors have no conflicts of interest to declare.
Statement of Authorship
BKV designed the study, collected data, coordinated the study, performed the statistical analysis, interpreted the data, drafted the initial manuscript, reviewed and revised the manuscript. ESS and ABPDS collected data, identified patients for inclusion and drafted the initial manuscript. DYT supervised the study and reviewed and revised the manuscript.
