Introduction

Sjögren’s syndrome is the second most common autoimmune rheumatic disease and is characterized by lymphocytic infiltration of the exocrine glands, causing their dysfunction and destruction, especially the salivary and tear glands, thus leading to dry mouth and dry eyes, which are known as sicca symptoms.^1-3 Sjogren's syndrome is a systemic disease that can compromise the musculoskeletal, peripheral and/or central nervous, cardiovascular, circulatory, respiratory, renal and gastrointestinal systems, among others, in 50-60% of patients.^1,2,4

The general prevalence of Sjögren’s syndrome is estimated to range from 0.3 to 1 per 1000 people,⁵ females are more often affected, with a female:male ratio of 9 to 1, and the maximum incidence is observed among individuals aged from 40 to 55 years.^3,5,6 In Colombia, the prevalence is 0.12% among patients over 18 years old, with a female:male ratio of 4.6:1, and the age group with the highest prevalence is that to 65-69 years (0.5%).⁷ In another study, in 6 cities in the country, the prevalence was 0.08% (95%CI: 0.02-0.27).⁸

Treatments for sicca symptoms include moisturizers, eye lubricants, ophthalmic cyclosporine, artificial saliva and muscarinic agonists such as pilocarpine, as well as nonpharmacological measures.^9-11 Inadequate management of dry eye can lead to complications such as surface wear, corneal perforation, conjunctivitis, keratitis and vision loss, while dry mouth can produce dysphagia, speech difficulties, an atrophic or fissured tongue, ulcers, stomatitis, oral candida and dental caries, resulting in quality of life deterioration and disability.^1-3

Sicca symptoms can be exacerbated by numerous medications, especially diuretics, antidepressants, neuroleptics, muscle relaxants, hypnotics, opioids, benzodiazepines, anti-histamines and antispasmodics, among others,^1,3,4,6 and many of these medications have antimuscarinic properties that contribute to the anticholinergic burden of patients. The anticholinergic burden is defined as the cumulative effect of taking one or more drugs capable of producing adverse antimuscarinic reactions,^12,13 which can include dryness of the skin and mucous membranes, constipation, urinary retention, mydriasis, delirium, cognitive deterioration and sedation, among others.^12,14,15 Scales developed to quantify the anticholinergic burden use equations and medication lists to classify and assign points according to the medications' antimuscarinic activity.^12,13,16

These tools present variations due to the different methodologies used for their preparation and validation, which may influence patient outcomes.^12,13,17 In a systematic review in 2015, the ACB (Anticholinergic Cognitive Burden Scale), ARS (Anticholinergic Risk Scale) and ADS (Anticholinergic Drug Scale) were identified as the most validated instruments¹³; however, no standardized quantification scale is available.^13,16

Concordance studies use different designs to evaluate the degree of agreement between two or more observers or between different methods, techniques or instruments on the same observed phenomenon. If one technique or instrument is considered the "gold standard", then the resulting concordance will be considered a measure of conformity. However, if no techniques or instruments are considered "gold standards" or references, then any concordance identified will serve as a measure of consistency.^18,19 Because no "gold standard" is available to quantify the anticholinergic burden or for comparison with other tools, this is a study of consistency. Some studies have shown that the anticholinergic burden increases the risk of mucosal dryness^20,21; therefore, the objectives of the study were to use the three most validated anticholinergic burden scales to assess the prescriptions of patients with Sjögren’s syndrome and to determine the degree of agreement between these scales, in addition, to characterize some of their sociodemographic, clinical, and pharmacological variables.

Materials and methods

An analytical study of consistency was performed with three anticholinergic burden scales and the drugs currently used by patients diagnosed with Sjögren’s syndrome according to a population database. This database collects information from approximately 8.5 million people affiliated with Colombia's Health System, including six health insurance companies, corresponding to approximately 30.0% of the active affiliate population of the contributing regime and 6.0% of patients registered with the state-subsidized health insurance regime in the country, representing 16.3% of the Colombian population.

The identification of the patients was made through the diagnosis of Sjögren’s syndrome from the 1st of July to the 30th of September 2019. The diagnosis was identified using the International Statistical Classification of Diseases and Related Health Problems (ICD-10), where M35.0 is the code for sicca (Sjögren) syndrome. Male and female patients older than 14 years of age who attended outpatient consultations were included. We analyzed the prescriptions of patients diagnosed with Sjögren’s syndrome who were receiving drugs with anticholinergic properties using the ADS, ACB and ARS.

Based on information regarding medication consumption among the affiliated population, which was systematically collected by the dispensing company (Audifarma S.A.), a database was designed to allow collection of the following groups of patient variables:

The protocol was approved by the Bioethics Committee of the Universidad Tecnológica de Pereira in the risk-free research category. The ethical principles established by the Declaration of Helsinki were respected. Patients' personal data were not considered.

The data were analyzed with the statistical package SPSS Statistics, version 24.0 for Windows (IBM, USA). A descriptive analysis was performed in which frequencies and proportions were used to describe qualitative variables, while measures of central tendency and dispersion were used for quantitative variables. Quantitative variables were compared using Student's t test or ANOVA, and the X² test was used for categorical variables. Binary logistic regression models were established using the consumption of drugs with an anticholinergic burden (1 or more points, according to the ADS, ACB and ARS) as the dependent variable, and variables that were significantly associated with these drugs in bivariate analyses as covariables. p<0.05 was set as the level of statistical significance.

Using the Epidat software version 4.2 of 2016, the concordance analysis was performed between the ADS, ARS and ACB using the weighted kappa coefficient with quadratic weights and a confidence interval (CI) of 95%. To classify the results, the scale described by Landis and Koch was used as follows: weak agreement, 0-0.2; mild agreement, 0.2-0.4; moderate agreement, 0.4-0.6; substantial or high agreement, 0.6-0.8; and almost perfect agreement, 0.8-1.²²

Results

A total of 15,696 patients diagnosed with Sjögren’s syndrome and distributed among 99 different cities were identified. The mean age was 65.4±13.9 years (range: 14.08-104.83 years), and 74.2% (n = 11,641) of the patients were women. The female:male ratio in the study population was 2.9:1. A total of 94.1% (n = 14,765) of the patients were receiving pharmacological treatment for Sjögren’s syndrome, with carboxymethylcellulose (n=3594, 22.9%) being the most prescribed eye lubricant, while oral pilocarpine was prescribed to 3.5% (n = 544) of patients. The use of synthetic disease-modifying antirheumatic drugs was identified in 8.3% (n = 1299) of the patients, while the use of biological drugs was identified in 0.3% (n = 46) of the patients (Table 1).

Consistency analysis

The ADS and ACB showed the best degree of agreement (kappa 0.6520; 95%CI: 0.6393-0.6648), while comparisons involving the ARS yielded low consistencies (Table 4).

Discussion

This study identified potentially inappropriate prescriptions of antimuscarinic drugs among patients diagnosed with Sjögren’s syndrome using three different anticholinergic burden scales and determined the degree of agreement between the scales. The findings may be useful for caregivers, scholars and scientists with respect to clinical decision-making regarding potential harmful interactions and adverse drug reactions experienced by patients. In Colombia, the ADS has historically identified an anticholinergic burden of 39.1% among patients with Sjögren’s syndrome.²³

The ACB identified the highest amount of drugs with antimuscarinic properties (37.5%), followed by the ADS (35.3%) and the ARS (25.2%). These findings are similar to those reported in Finland by Tiisanoja et al. in patients with xerostomia, where antimuscarinic prescriptions were mostly identified by the ACB (33.7%), followed by the ADS (29.6%) and ARS (28.9%).¹⁷ Identifying these drugs is important because the number of adverse antimuscarinic reactions increases with a higher anticholinergic burden; however, no evidence indicates that the association is linear, and ultimately, a plateau most likely occurs when burden values become very high.¹²

In another study conducted in Finland, Tiisanoja et al. found that a score of 3 or higher on the ADS was a risk factor for developing xerostomia (risk ratio (RR): 3.17:95%CI:1.44-6.96).²⁰ Based on a list of drugs with anticholinergic properties, Rudolph et al. found that patients with a high anticholinergic burden had an increased risk (OR:1.9; 95% CI:1.50-2.50) of experiencing adverse peripheral effects (xerostomia, xeroph-thalmia and constipation).²¹ No studies relating ACB scores with an increased risk of mucosal dryness are available.

When comparing the three tools, the ADS and ACB showed the best agreement (0.65). In contrast, the degree of agreement between the ACB and ARS and between the ADS and ARS was low. Discrepancies between these scales may be related to how they were developed, the associated methodologies and validation measures, the number of drugs listed in each instrument, differences in the classification of the antimus-carinic potency of each drug and the inclusion of routes of administration other than oral or parenteral.^21,24,25

No consistency studies comparing anticholinergic burden scales specifically among patients with Sjögren’s syndrome have been identified. However, some studies have been conducted in different populations and clinical contexts.^26-29 Naples et al. found the best agreement between the ADS and ACB (0.70) for seniors living at home in the USA.²⁶ Pont et al. found the highest degree of agreement between the ADS and ACB (0.62) for nonhospitalized men in Australia,²⁷ and Turró-Garriga et al. identified high concordance between the ADS and ACB (0.62) for patients with dementia in Spain.²⁹ However, in other research conducted in Spain, Lertxundi et al. found the best agreement between the ACB and ARS (0.25) in patients hospitalized for psychiatric disorders.²⁸ Possible explanations for this discrepancy may include differences in the characteristics of the population (community, hospitalized and specific population groups) and the inclusion of medications in the instruments that are not available in all countries.

Related to the above, the multivariate models used to find the variables that were related to anticholinergic load, calculated with the ADS, ACB and ARS scales, showed risk or protective associations that varied according to the tool used (see supplementary tables). These discrepancies were also evidenced in a study that compared the three anticholinergic burden scales, but in patients with vertebral and non-vertebral fractures.³⁰

Anticholinergic drugs are necessary in the treatment of various pathologies, such as overactive bladder, urinary incontinence, chronic obstructive pulmonary disease, asthma, Parkinson's disease, psychotic disorders, mood disorders and allergic reactions.¹⁴ Anticholinergic burden scales are tools that help guide clinical decision-making, allowing clinicians to stop or change a drug with potent antimuscarinic activity in favor of another drug with little or no burden and thus guaranteeing greater safety and a lower probability of adverse reactions.¹⁴ In recent years, problems related to prescribing practices have attracted increasing interest, which has promoted the development of tools for more appropriate drug prescription practices, such as the Beers criteria³¹ and the STOPP (Screening Tool of Older Person's Prescriptions),³² which include anticholinergic medications.^31,32

In this study, most patients received useful topical prescriptions for the management of sicca symptoms, which is consistent with the recommendations of different clinical practice guidelines.^9-11 The use of oral pilocarpine (3.5%) differed from that found in other studies (20-31.7%).^33,34 These differences are probably due to the prescribing habits of physicians, the availability or lack of such drugs in the health systems of various countries or the degree of xerostomia and xerophthalmia severity among patients included in the studies.

Some limitations related to the interpretation of the results should be noted. Clinical histories were not obtained to identify nonpharmacological management measures used by patients, the evolution of the disease was not considered, the classification of the disease as a primary or secondary diagnosis was not determined, and possible complications experienced by patients were not evaluated. Furthermore, whether some of the possible adverse effects actually occurred was not investigated. In addition, the diagnosis of sicca (Sjögren) syndrome found in the ICD-10 can be used in patients with symptoms secondary to adverse drug reactions as well as to chemotherapy or radiotherapy. On the other hand, as a specific limitation of cross-sectional studies, it was found that the different variables were collected at a certain point in time, therefore the anticholinergic load and the pharmacological treatment of patients with Sjögren’s syndrome are distributed in a 3-month period and not throughout the course of the disease.

Conclusions

Based on the above findings, we found little agreement between the three scales gauging the anticholinergic burden, although greater consistency was found between the ADS and ACB. Therefore, additional studies are needed to determine how these differences may impact clinically relevant outcomes such as mucosal or skin dryness, among others. Most patients received topical treatments for Sjögren’s syndrome according to clinical practice recommendations. These results should be useful to promote and strengthen educational and pharmacovigilance strategies that improve the prescription habits of physicians involved in the care of these patients.