The profile of comorbid conditions and the structure of mortality in patients with rheumatoid arthritis in the Stavropol Territory: preliminary results

Introduction

Rheumatoid arthritis (RA) continues to be associated with high mortality rates. The increased mortality of patients with RA is mainly due to concomitant diseases, among which a special place is occupied by cardiovascular diseases (CVDs) [1], infections [2], kidney pathology [3], respiratory diseases [4], and oncopathology [5]. Despite significant progress in the management of RA, the burden of comorbid pathology for these patients remains a serious problem.

The last decade has brought a new understanding of comorbidity associated with RA [1]. Comorbid pathologies are considered independent predictors of increased mortality in RA [6]. Convincing evidence demonstrates that people with RA are 80% at high risk of developing one or more comorbid conditions [7][8]. These pathologies may have atypical signs, are difficult to diagnose and poorly treatable [9][10]. Comorbid conditions can affect the activity of RA, become an obstacle to optimal control of the disease, and lead to an increased risk of death of patients [11][12].

Today, there is information confirming a decrease in the frequency of deaths of patients with RA [13][14]. There is even evidence that the mortality rate in RA patients is similar to that in patients in the general population [15]. At the same time, other studies continue to show that mortality in patients with RA is significantly higher or that the mortality gap with the total population tends to increase [16]. The reasons for the differences in mortality rates can be explained by the change in the principles and tactics of treatment of patients with RA over the past decade, as well as the peculiarities of ethnicity [17][18] and the different structure of the analyzed cohorts of patients [19], which requires an assessment of the risk of mortality in patients with RA in real clinical practice.

Given the significant spread of digital data, the lack of clear national and regional registers characterizing the state of the problem of comorbidity and mortality of patients with RA, including in dynamics, a key role in this regard should be given to periodic epidemiological studies, including a description of how the disease manifests itself in a particular cohort (incidence, comorbidity, mortality, trends in time, and regional features).

The purpose of the study was to study the comorbid background and mortality structure of RA patients in the Stavropol Territory in a cohort of patients of the Stavropol Regional Clinical Hospital in the period of 2015–2021.

Materials and methods

The study included 998 patients (107 men and 891 women, average age – 54.1±1.41 years) with a reliable diagnosis of RA, established according to the classification criteria ACR/EULAR (2010) [20]. All patients were treated at the rheumatology center of the Stavropol Territory State Budgetary Healthcare Institution “Stavropol Regional Clinical Hospital” (SRCH) in the period of 2015–2021. All patients received voluntary informed consent to participate in the study according to the Helsinki Declaration of the World Medical Association (WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects, 2013) and the processing of personal data.

After the formation of the register of patients with RA, the next endpoint was evaluated — the onset of a fatal outcome from any cause. Autopsy protocols for 2015–2021 in the pathology department of the SRCH were analyzed. The fatal outcomes of patients with RA in the pathoanatomic diagnosis were studied. The results were qualitative data in the form of relative frequencies (%).

To compare the results obtained with the data of modern literature, a search and a systematic review of sources of 2018–2022 was conducted using various combinations of keywords (“rheumatoid arthritis”, “comorbid conditions”, “epidemiology”, “cohort study”). Online search of literary data was carried out in available databases, such as Elibrary, Pubmed, Scopus, and ScienceDirect.

Results

The results of the analysis of the frequency and structure of comorbid pathology of patients with RA, conducted on the basis of data from a systematic review of literature sources (2018–2022), are summarized in Table 1.

The spectrum of comorbid conditions registered by researchers in patients with RA is quite wide and includes heart disease, hypertension, respiratory diseases, diabetes mellitus, gastrointestinal diseases, kidney pathology, osteoporosis, malignant neoplasms and infections.

The table clearly shows that the data on the occurrence of comorbid conditions in patients with RA vary in a very wide range from different sources. In the bulk of the sources, the leading position in terms of prevalence is occupied by either acute respiratory infections or respiratory pathologies. At the same time, the spread of data on the occurrence of these comorbid conditions is significant and ranges from 11.1% to 87.6% and from 3.41% to 40.0%, respectively.

The nature of comorbidity of patients diagnosed with RA in the Stavropol Territory is presented in the form of a diagram in Figure 1.

The leading place in the structure of comorbidity of RA patients in the cohort of SRCH patients was occupied by coronary heart disease (35.29%). Respiratory diseases were registered in the second place in this sample (29.41%). The representation of “Blastomatosis” and COVID-19 in comorbidity was 11.75% of patients each. The share of pathologies such as hypertension, diabetes mellitus, and autoimmune thyroiditis accounted for 5.88% of patients.

The frequency of determining causes of deaths was calculated for the number of patients with a verified cause. The structure of the conditions of fatal patients with RA is shown in the diagram (Figure 2).

Acute myocardial infarction (40.0%) was registered as the leading cause of deterioration of the condition of patients with RA in the SRCH cohort, which led to death. The remaining documented pathologies in this aspect, in order of decreasing frequency of their occurrence, were distributed as follows: viral pneumonia (20.0%) > breast cancer (13.3%), sepsis (13.3%) > thyroid cancer (6.67%), hemorrhagic stroke (6.67%).

Discussion

RA is a severe progressive disease that leads to deterioration of the functional status of the patient, disability, and an increase in the mortality rate. The prevalence of this pathology implies the presence of concomitant pathologies in patients and, accordingly, a burdened comorbid background. Concomitant diseases may appear before the development of RA, during exacerbation or remission, and may also be a complication of chronic inflammation or its drug treatment [32]. The comorbid background is an important aspect of observation and correction in patients with RA due to its significant influence on the course of the disease and its outcome [33]. Comorbid conditions should be taken into account due to a known or suspected association with certain classes of drugs. In clinical practice, it is extremely important to balance the potential benefits of RA treatment with the possible risk of concomitant diseases [2]. Therefore, an adequate and timely assessment, identification, and correction of comorbid risk components are required.

The authors’ review of the latest scientific data indicated a high percentage of cardiovascular and respiratory pathologies, gastrointestinal diseases, metabolic disorders (diabetes mellitus, osteoporosis), oncological and infectious load in patients with RA. At the same time, there is no common uniform regular structure of the comorbid profile in RA. The occurrence and structure of comorbid conditions vary in a very wide range of indicators. There is a pronounced geographical dependence, ethnic, cohort, and age characteristics.

The structure of comorbidity of patients with RA in the Stavropol Territory in the cohort of SRCH patients included coronary heart disease (CHD), autoimmune thyroiditis (AT), respiratory diseases, hypertension (HT), “Blastomatosis”, diabetes mellitus (DM), and COVID-19 infection. The comorbidity profile of patients with RA, in order of decreasing frequency of occurrence of the pathological condition, had the following form: CHD > RH > (“Blastomatosis”, COVID-19) > (AT, HT, DM) and logically determined the structure and frequency of the onset of conditions that led to the fatal outcome of patients with RA.

The problem of studying the mortality of RA patients is a difficult task, since the registration of the causes of death of these patients often occurs without a diagnosis of RA. In practice, only a part of pathological conditions requiring therapeutic and diagnostic measures are included in the main diagnosis, the rest are registered as concomitant, and often are not included in clinical and pathoanatomic diagnoses at all. This is especially true for long-term chronic processes, which are rheumatic diseases, in particular RA [34].

Taking this into account and the availability of not always unambiguous literature data, there is an obvious need to assess the risk of mortality in patients with RA in real clinical practice.

For the Stavropol Territory, almost 50% of the conditions that led to the fatal outcome of patients with RA were cardiovascular pathologies (acute myocardial infarction – 40.0%; hemorrhagic stroke – 6.67%). These data turned out to be relatively comparable with the current assessment in this regard in other regions of Russia and countries. According to the results of large cohort studies, cardiovascular mortality in RA ranges from 15 to 50% [6][35]. The magnitude of the risks of death from CVDs varies in different studies, which may be related both to the characteristics of the studied cohorts of patients and the effectiveness of achieving or not achieving the goal of treatment, as well as to the characteristics of the therapy performed.

New CVD treatment strategies have a positive effect on reducing the mortality of patients with RA [36]. Today, a number of researchers [13][14] have revealed a reduction in the risk of death of RA patients from CVDs.

The results of this study contrast somewhat with these empirical data. The share of CVD in the structure of conditions that led to the mortality of RA patients is in the first place and is relatively high. The trend towards a decrease in the mortality of patients with RA in the Stavropol Territory of the SRCH cohort has not yet been expressed, which suggests that the development and implementation of updated guidelines on cardiovascular risk management in this aspect could be beneficial.

Other conditions that led to the death of patients with RA in the SRCH cohort were neoplasms, viral pneumonia, and sepsis.

The given results on the mortality rate of RA patients caused by oncopathology did not fall out of the range of data from cohort studies and meta-analytical reviews of the last five years [5][14][23]. At the same time, in the cohort of RA patients studied by the authors, in 6.67% of cases, death occurred due to thyroid cancer, and in 13.3% of cases, it was caused by breast cancer. This to some extent goes against a number of data [1], according to which patients with RA differ in reducing the risk of breast cancer.

The relatively high frequency of deaths of patients with RA due to viral pneumonia documented in the authors’ retrospective analysis (20.0%) fits into the range of data from other researchers and logically agrees with the above data of the comorbid background, in the structure of which COVID-19 infection ranked third along with oncopathologies. The revealed fact to some extent echoes the data of Varela et al. [31], according to which, in the cohort of patients with established RA, the main causes of death were CVDs and COVID-19 infection.

Sepsis was registered as the fourth leading cause of death of patients with RA in the SRCH cohort. RA itself is known to be independently associated with increased mortality from sepsis. In the structure of the causes of deaths in RA patients, a high proportion of sepsis (31.4%) is distinguished with its pronounced tendency to increase in recent years [37][38]. This may be quite logical due to the high infectious risk characteristic of RA, due to a general violation of the immune system characteristic of autoimmune diseases, combined with the iatrogenic effect of corticosteroids and immunosuppressive drugs. Cohort studies often report the development of severe infections and septic shock in patients with RA against the background of the use of anti-rheumatoid medicines [39].

At the same time, the authors of this particular study registered a relatively low proportion of deaths of patients with RA due to sepsis (13.33%). Interpreting the obtained results in the light of the available literature over the past few years, the authors found only one study [40] involving patients with RA and showing a mortality rate caused by sepsis (14%), almost similar to that in the cohort of patients studied by the authors. This difference in results is probably due to the peculiarities of therapeutic tactics in severe infections and the appointment of basic disease-modifying antirheumatic medicines (DMAMs). There is evidence [40, 41] that the use of biological DMAMs in comparison with synthetic DMAMs significantly reduces the risk of sepsis and death after severe infection in patients with RA. However, this can only partially explain the features of the data obtained in this study, since the authors were unable to obtain complete information about the number of patients receiving biological DMAMs, in particular information about the timing of the appointment and duration of use of these medicines.

Conclusion

Thus, in this particular research, the authors attempted to obtain and analyze fresh information on the prevalence and spectrum of comorbid conditions, as well as data on the structure of mortality in patients of the Stavropol Territory SRCH cohort with an established diagnosis of RA. The data obtained carry information that can be used by rheumatologists to optimize the management strategy of RA and the risk of comorbid conditions.

The main advantage of the study was that the study included patients with a reliably established diagnosis of RA. This approach prevented the omission of deaths of patients with undiagnosed RA. In addition, information from surveys and self-reports of patients was not processed, but accurate data from medical databases and documentation were used. The weak side of this work was the costs of the retrospective nature of the study. It was not possible to get the full range of necessary information. In particular, information about bad habits, stress, employment status, and socio-demographic factors, which, according to a number of opinions [6][42], can influence the outcome of RA and are considered independent predictors of mortality in this pathology, were not taken into account. This placed the results of this research in the rank of preliminary and determined the tasks of further research.