Age, Urban-Rural, Gender and Sex-Based Differences in Autoimmune and Autoinflammatory Diseases: A Cross-Sectional Study

doi:10.21203/rs.3.rs-7991120/v1

Background: There are no studies that explored globally and exhaustively the relationship between the age group, urban-rural, gender and sex and the autoimmune diseases’ nosological entity, autoimmune diseases’ nosological sub-entities, each of the autoimmune diseases and autoinflammatory diseases’ nosological entity, autoinflammatory diseases’ nosological sub-entities, each of the autoinflammatory diseases.

Objective: To determine globally and exhaustively the age, urban- rural, gender and sex-based differences in autoimmune diseases and autoinflammatory diseases.

Design: 15-year cross-sectional study.

Setting: A hospital based study (Department of internal medicine at the University Hospital Center of the Point G)

Participants: 317 patients presented autoimmune and/or autoinflammatory diseases.

Measurements: Bivariate analysis using the Chi-square and Fisher´s exact tests to assess the statistical significance and strength of the associations between the categorical independent variables and the outcome variables.

Results: The age group of 20 – 39 years was significantly associated with autoimmune diseases (p= 0.000) while the age group of 60 – 79 years was significantly associated with autoinflammatory diseases (p= 0.000). The systemic autoimmune diseases were more frequently diagnosed in females than in males (p=0.000). The females were 2.45 times more likely than the males to have the organ-specific autoimmune diseases (p=0.001). The males were 2.04 times more likely than the females to develop polygenic autoinflammatory diseases (p= 0.033). The systemic autoimmune diseases were more prevalent in patients living in urban areas (44 cases) than in patients living in rural (26 cases), (p= 0.347). The patients living in urban were more likely than the patients living in rural areas to have the organ-specific autoimmune diseases (p= 0.320). The patients living in urban areas were more likely than the patients living in rural areas to have the polygenic autoinflammatory diseases (p= 0.469).

Limitation: Single-center study, which may hamper generalizability.

Conclusion: Our study demonstrates the existence of several relevant positive associations between the age group, urban-rural, gender and sex and the autoimmune diseases’ nosological entity, autoimmune diseases’ nosological sub-entities, each of the autoimmune diseases and autoinflammatory diseases’ nosological entity, autoinflammatory diseases’ nosological sub-entities, each of the autoinflammatory diseases.

Gastroenterology & Hepatology

Urology & Nephrology

Ophthalmology

Gender

sex

urban-rural

age

autoimmune diseases

autoinflammatory diseases

Autoimmune and autoinflammatory diseases are a large heterogeneous group of inflammatory diseases that have in common the chronic inflammatory process but their clinical and biological expressions are extremely variable [1]. Autoimmune diseases are defined as all pathological manifestations linked to the involvement of effectors of the immune system, B lymphocytes and T lymphocytes, specific to the antigens of the organism to which this system belongs (self-antigens) [2]. They are very heterogeneous and are usually classified into two groups: systemic autoimmune diseases and organ-specific autoimmune diseases [3]. As for auto-inflammatory diseases, they are due to an abnormality of innate immunity. There are no elevated or pathogenic autoantibodies and no activated T-lymphocytes, as opposed to autoimmune diseases. They are subdivided into two groups: monogenic autoinflammatory diseases and polygenic autoinflammatory diseases [4–6]. However, the polygenic autoinflammatory diseases can also be subdivided into two groups: systemic polygenic auto-inflammatory diseases and organ-specific polygenic auto-inflammatory diseases according to their clinical phenotype [7].

Several studies demonstrated that most of autoimmune diseases occurred in young adult [8, 9]. Indeed, autoimmune diseases are among the leading causes of death among young and middle-aged women in the United States. The underlying mechanism remain an opened research question in the literature. However, the sex-hormone upregulation et environment factors as endocrine-disrupting chemicals are more and more described to be associated to the autoimmune diseases occurrence and so that the young adults are more likely than others age groups to be exposed [10, 11]. The monogenic auto-inflammatory diseases are exceptional in sub-Saharan Africa but cases are commonly reported in North Africa [12]. The polygenic autoinflammatory diseases such systemic sarcoidosis occurred frequently in the age group of 20–45 years old for males and 50–65 years old for females [13], Still onset diseases with the median age 42 years for females and 39 years for males [14].

Epidemiological data from published works suggest that sociocultural gender based differences in autoimmune diseases and autoinflammatory diseases are a neglected area in the literature, on the one hand and there are more reporting biases based on confusion between sociocultural determinants (gender) and biological determinants (sex), on the other hand. Indeed, some studies report that lower education level in women, higher smoking rates in men, and environmental exposure in men are gender related determinant associated to autoimmune diseases [15–17]. In addition, tertiary referral center accessibility was found to be positively correlated to poor management of sarcoidosis, an autoinflammatory diseases [18].

It is long been appreciated that the majority of autoimmune diseases occurred in women than in males. This support that females are more susceptible to autoimmune diseases than males. Sex-based immunological and hormonal differences could contribute to the difference in diseases susceptibility [10, 19, 20]. Some polygenic autoinflammatory diseases occurred frequently in females than in males, sarcoidosis [18], adult-onset Still’s disease [21] and those in males than in females, gout [22].

The sociocultural, and the environmental factors and their long-term interaction with genetic and epigenetic factors leading immune-endocrine dysregulation may be different between urban and rural area. These may explain the differences observed in some diseases between urban and rural area. Indeed, the urban-rural based differences in autoimmune and autoinflammatory diseases are less investigated. However, Allen et al. reported that a diagnosis peak of Type 1 diabetes, an autoimmune disease, in the third and fourth quarter among rural cases contrasted with even quarterly distribution among urban cases [23]. In addition, Kajdasz et al. demonstrated that a number of rurally-linked exposures were found to be univariately associated with the development of sarcoidosis, a polygenic autoinflammatory diseases [24].

Taken together, although research works investigated the relationship between the age group, urban-rural, gender and sex-based differences and certain autoimmune and autoinflammatory diseases taken individually. However, there are no studies that explored globally and exhaustively this relationship between the age group, urban-rural, gender and sex and the autoimmune diseases’ nosological entity, autoimmune diseases’ nosological sub-entities, each of the autoimmune diseases and autoinflammatory diseases’ nosological entity, autoinflammatory diseases’ nosological sub-entities, each of the autoinflammatory diseases. In addition, these aspects are less studied in Africa, particularly in Mali.

Therefore, there is a crucial need to more explore the relationship of age, urban-rural, gender and sex-based differences in autoimmune and autoinflammatory diseases and furthermore to identify its specific determinants associated with autoimmune and autoinflammatory diseases. So, the research strategy that aims to explore these aspects would contribute to identify new therapeutic targets and to adapt treatment and preventive strategies. We aimed in this work to determine age, urban- rural, gender and sex-based differences in autoimmune diseases and autoinflammatory diseases in internal medicine department at the University Hospital Center of the Point G.

Research questions

The study addresses two research questions, namely: 1) Are there relevant significant associations between the age, urban-rural, gender and sex and the autoimmune diseases’ nosological entity, autoimmune diseases’ nosological sub-entities and each of the autoimmune diseases? 2) Are there relevant significant associations between the age, urban-rural, gender and sex and autoinflammatory diseases’ nosological entity, autoinflammatory diseases’ nosological sub-entities and each of the autoinflammatory diseases?

Study design

A cross-sectional study with retrospective data collection was conducted to explore the age, urban-rural, gender and sex-based differences in autoimmune and autoinflammatory diseases. The study strictly adhered to the cross-sectional reporting guidelines of Strengthening of Reporting of Observational Studies in Epidemiology (STROBE) [25].

Study setting

Bamako is the capital and largest city of Mali. Mali is a West African country, comprising 19 administrative regions. Mali is a developing country that is currently 184th out of 189, United Nations Human Development Index 2019. Mali’s population is estimated at 22 million 395 thousand 485 inhabitants, including : 47.2% of young people under the age of 15 ; 49.9% of people aged 15 to 64, according to the Fifth General Census Of The Population And Housing in Mali. Mali has one of the highest fertility rates in the world, with over six children per woman in 2018. Since January 2016, the guaranteed minimum salary (SMIG) is 40,000 FCFA (US$80). More than 20% of the country’s population live in urban areas and more than 60% in rural areas. In Mali, the Health care is organized into three levels: the district health level (community health centers and reference health centers), the second level represents the regional hospitals, and the third level is anchored by the national hospitals and university hospital centers (UHC). Among the third level the University Hospital Center of the Point G where the present study was conducted between January 1, 2005 to December 31, 2019, which is 15 years. It is located in Bamako. This department of internal Medicine, known as center of excellence for diagnosis and management of autoimmune and autoinflammatory diseases, is held by educators, researchers, and practioner internists. A total of 6383 patients were hospitalized during the study period.

Study population

We included in this study all the medical records of patients hospitalized for autoimmune and/or autoinflammatory disease during the study period. We did not include in this study the outpatients, and the patients hosipitalized with the diagnosis of autoimmune and/or autoinflammatory diseases in the internal medicine department at the University Hospital Center of the Point G outside the study period.

Variables

The independent study variables were the socio-demographic data which included sex, age, profession, and residency. Autoimmune diseases’ nosological entity, its nosological sub-entities and each of the autoimmune diseases; and autoinflammatory diseases’ nosological entity, its nosological sub-entities, and each of the autoinflammatory diseases are the dependent (outcome) variables, for which diagnoses were established on the basis of clinical and paraclinical data and/or validated diagnostic criteria according to the type of autoimmune and autoinflammatory diseases.

Data collection

A pre-established survey form was designed and used to collect data on the sociodemographic and clinical characteristics. Sociodemographic variables such as sex, age, profession/gender related occupation, residency and clinical variables such as discharge diagnosis were collected from medical records and registry of hospitalization used for medical record identification.

Difficulties and biases

During this study, we encountered certain problems related to the lack of information in the medical records. Some clinical hypothesis of autoimmune and autoinflammatory diseases were not confirmed because of financial difficulties to perform speficific tests.

Sampling and sample size

This was an exhaustive sampling of all cases of hospitalization for autoimmune and/or auto-inflammatory diseases during the study period. The sample size was not calculated.

Statistical methods

The collected data were entered into SPSS version 22 software for cleaning and analysis. Data cleaning was done by checking and correcting for duplicates and completing missing data, and correcting outliers. We used Microsoft Excel to generate bar graphs. We conducted statistical analyses using Epi Info version 7.2 and SPSS version 22 software. We conducted univariate analysis to obtain mean and standard deviation for quantitative data and numbers and percentages for qualitative data. In the bivariate analysis, we calculated odds ratios (OR), 95% confidence intervals (C.I), and p-values. The outcome variables of interest for bivariate analysis were autoimmune diseases’ nosological entity, autoimmune diseases’ nosological sub-entities, each of the autoimmune diseases and autoinflammatory diseases’ nosological entity, autoinflammatory diseases’ nosological sub-entities, each of the autoinflammatory diseases. The categorical independent variables of interest were age group, sex, profession, and residency. The Chi-square (uncorrected and corrected) and Fisher´s exact tests were used to assess the statistical significance and strength of the associations between the categorical independent variables and the outcome variables. A two-tailed p-value < 0.05 were retained and considered as statistically significant.

Ethical consideration

According to Helsinki guideline, research involving human subject should be conducted ethically, with the well-being of the subject taking priority over scientific or societal interests. Our research study aiming to provide a cross-sectional data on the relationship between age group, urban-rural, gender and sex-based differences and all autoimmune and autoinflammatory diseases the internal medicine department involved human subjects. However, we used secondary data on patient’s medical records (sociodemographic and clinical data) and did not use the biological specimens.

In addition, the study was retrospective and all data was extracted anonymously from the medical records and registry of hospitalization. Therefore, patients’ informed consent was not required.

Given the nature of the study, formal ethical approval from an ethics committee was not sought. However, formal permission to conduct this study was obtained from the General Director of University Hospital Center of the Point G. The medical records and registry of hospitalization were returned in the archive room immediately after exploitation.

Characteristics of the study participants

During a fifteen-year study period, 331 cases of autoimmune diseases and/or autoinflammatory diseases including 07 cases of associations were noted from 317 medical records. These were 291 cases of autoimmune diseases and 40 cases of autoinflammatory diseases. Socio-demographic data are illustrated in the figure S1 (Supplementary Appendix). Out of the 317 medical records included in the study, the female represented 65.0% of cases with a sex-ratio of 0.54. The age group of 20 – 39 years accounted for 50.2% of the study population; the mean age of patients was 35.3 ±16.3 years; and the extreme ages were 07 and 79 years. Houseworkers were found in 37.2% of cases. Patients came from urban areas in 65.5% of cases.

Age-based differences in autoimmune and autoinflammatory diseases

Table 1 summarizes the comparison of patients between the different age groups and the autoimmune and autoinflammatory diseases. The age group of 20 – 39 years was significantly associated with autoimmune diseases (153 cases; OR= 5.02; 95% CI= 2.01 – 12.57; p= 0.000). The age group of 60 – 79 years was significantly associated with autoinflammatory diseases (16 cases; OR= 8.13; 95% CI= 3.75 – 17.61; p= 0.000).

Gender-based differences in autoimmune and autoinflammatory diseases

Comparison of patients between the sex and the profession are mentioned in figure S2 (Supplementary Appendix). The profession as houseworkers were exclusively for the females (118 cases vs. 0) and farmers and workers for the males (24 cases vs. 0 and 15 cases vs. 1 cases, respectively). Table 2 shows the comparison of patients between the profession and the autoimmune and autoinflammatory diseases. There was no significant correlation between the houseworkers and autoimmune diseases (109 Houseworkers; OR= 1.58; 95% CI= 0.71 – 3.55; p= 0.261), and between the farmers and autoimmune diseases (19 farmers; OR= 0.39; 95% CI= 0.13 – 1.12; p= 0.080). Auto-inflammatory diseases occurred more frequently in houseworkers (9 houseworkers; OR= 0.45; 95% CI= 0.21 – 0.98; p= 0.039). The farmers were 2.54 times more likely to develop autoinflammatory diseases than others professions (6 farmers; OR= 2.54; 95% IC= 0.94 – 6.84; p= 0.114).

Sex-based differences in autoimmune and autoinflammatory diseases

Table 3 summarizes the comparison of patients between the sex and the autoimmune diseases. The systemic autoimmune diseases were more frequently diagnosed in females than in males (63 cases vs. 7 cases; 0R= 0.15; 95% CI= 0.07 – 0.35; p=0.000). The systemic autoimmune diseases found were dominated by systemic lupus erythematosus (3 males vs. 40 females, p= 0.000), rheumatoid arthritis (3 males vs. 13 females, p= 0.162). The females were 2.45 times more likely than the males to have the organ-specific autoimmune diseases (90 cases vs. 131 cases; OR= 2.45; 95% CI= 1.41– 4.27; p=0.001). Type 1 diabetes (64 males vs. 77 females; OR= 2.28; 95% CI= 1.43 – 3.65; p= 0.001) and Graves’disease (10 males vs. 38 females, OR= 0.44; 95% CI=0.20 – 0.92; p= 0.025) were the commonest organ-specific autoimmune diseases.

Comparison of patients between the sex and the autoinflammatory diseases are mentioned in table 4. There were no cases of monogenic autoinflammatory diseases in our study. The males were 2.04 times more likely than the females to develop polygenic autoinflammatory diseases (20 cases vs. 20 cases; OR= 2.04; 95% CI= 4.52 – 3.99; p= 0.033). The systemic polygenic autoinflammatory diseases were 3.19 times more likely to be found to be in males than in females (5 cases vs. 3 cases; OR= 3.19; 95% CI= 0.75 – 13.61; p= 0.134). These systemic polygenic autoinflammatory diseases were dominated by systemic non autoimmune vascularitis (5 cases vs. 1 case; OR=9.67; 95% CI= 1.12 – 83.83; p= 0.021). Organ-specific polygenic autoinflammatory diseases were more common in females than in males (15 cases vs. 17 cases; OR= 1.74; 95% CI= 0.83 – 3.63; p= 0.138). Among the organ-specific polygenic autoinflammatory diseases, the chronic inflammatory rheumatism (11 cases vs. 11 cases; p= 0.127): gout as microcrystalline arthropathies (8 cases vs 8 cases; p= 0.197) and spondylarthropathies (2 cases vs. 1 case; p= 0.281); and the Chronic inflammatory bowel disease (4 cases vs. 6 cases; p= 0.000) were more prevalent.

Urban-rural based differences in autoimmune and autoinflammatory diseases

Table 5 summarizes comparison of patients between the residency and the autoimmune diseases. The systemic autoimmune diseases were more prevalent in patients living in urban areas at the time of diagnosis (44 cases) than in patients living in rural (26 cases), (0R=0.77; 95% CI=0.44 – 1.33; p= 0.347). There were no statistically significant differences between patients living in urban areas and patients living in rural areas in regards to systemic autoimmune diseases as systemic lupus erythematosus (28 cases vs. 15 cases; p= 0.719), Rheumatoid arthritis (11 cases vs. 15 cases; p= 0.913). The patients living in urban were more likely than the patients living in rural areas to have the organ-specific autoimmune diseases (153 cases vs. 68 cases; OR= 1.29; 95% CI= 0.78 – 2.14; p= 0.320). Type 1 diabetes (101 patients living in urban vs. 40 patients living in rural areas; p= 0.161) and Graves’disease (35 patients living in urban vs. 23 patients living in rural areas; p= 0.385) were the commonest organ-specific autoimmune diseases.

Comparison of patients between the residency and the autoinflammatory diseases are mentioned in table 6. The patients living in urban areas were more likely than the patients living in rural areas to have the polygenic autoinflammatory diseases (25 cases vs. 15 cases; OR= 0.78; 95% CI= 0.39 – 1.54; p= 0.469). There were no statistically significant differences between patients living in urban areas and patients living in rural in regarding systemic polygenic autoinflammatory diseases (4 cases vs. 4 cases; p= 0.281). These were dominated by systemic non autoimmune vascularitis (3 patients living in urban vs. 3 patients living in rural areas; p= 0.394). Organ-specific polygenic autoinflammatory diseases were more frequent in patients living in urban areas than in patients living in rural areas (21 cases vs. 11 cases; OR= 0.91; 95% CI= 0.42 – 1.97; p= 0.810). Among the organ-specific polygenic autoinflammatory diseases, the chronic inflammatory rheumatism (16 patients living in urban areas vs. 6 patients living in rural areas; p= 0.588): gout as microcrystalline arthropathies (11 patients living in urban areas vs 5 patients living in rural areas; p= 0.913) and spondylarthropathies (2 patients living in urban areas vs. 1 patients living in rural areas; p= 1.000); and the Chronic inflammatory bowel disease (5 patients living in urban areas vs. 5 patients living in rural areas; p= 0.391) were more represented.

Main findings

The result from our 15-year cross-sectional study revealed the existence of the age-, urban-rural, gender- and sex-based differences in autoimmune and autoinflammatory diseases. To our knowledge, it is the first study that has explored these aspects globally and exhaustively.

Characteristics of the study participants

This study showed that the overall hospital frequency of autoimmune diseases and autoinflammatory diseases was slightly low, females were more represented than males, study populations were younger. These results are in line with findings from previous studies [26–28]. In addition, autoimmune diseases and autoinflammatory diseases are part of rare diseases except some cases such rheumatoid arthritis, and autoimmune thyroiditis [29, 30].

Age-based differences in autoimmune and autoinflammatory diseases

Autoimmune diseases are defined as all pathological manifestations linked to the involvement of effectors of the immune system, B lymphocytes and T lymphocytes, specific to the antigens of the organism to which this system belongs (self-antigens). In contrast, auto-inflammatory diseases are due to an abnormality of innate immunity [2, 4]. To our knowledge, there are no epidemiological data from published work seeking age group-, urban-rural-, gender- and sex-based differences in these two major nosological entities and their sub-entities: autoimmune diseases (systemic autoimmune diseases and organ-specific autoimmune diseases) and autoinflammatory diseases (monogenic autoinflammatory diseases and polygenic autoinflammatory diseases), but several evidence studied individually different autoimmune and autoinflammatory diseases. The age group of 20–39 years was significantly associated with autoimmune diseases, this is in concordance with previous studies [8, 9, 31]. Several studies showed that certain autoinflammatory diseases were more likely to be diagnosed in elderly than other age groups, in accordance with our study [13, 32]. In contrast, certain autoinflammatory diseases were more diagnosed in younger old years [14, 13].

Gender-based differences in autoimmune and autoinflammatory diseases

Gender generally refers to socially constructed roles, behaviors, and identities of women, men and gender-diverse people that occur in a historical and cultural context and may vary across societies and over time. Gender influences how people view themselves and each other, how they behave and interact and how power is distributed in society [33].

In our study, the profession as houseworker was exclusively for the females, and farmer and worker for the males, which strongly indicate that some occupational are devoted either in males neither in females. There was significant correlation between the houseworker and autoinflammatory diseases. Houseworker-specific determinants associated with autoinflammatory diseases should be more explore in large cohort study.

Sex- differences in autoimmune and autoinflammatory diseases

Sex generally refers to a set of biological attributes that are associated with physical and physiological features (e.g., chromosomal genotype, hormonal levels, internal and external anatomy). A binary sex categorization (male/female) is usually designated at birth ("sex assigned at birth"), most often based solely on the visible external anatomy of a newborn [33].

In our study, the systemic autoimmune diseases were more frequently diagnosed in females than in males. The systemic autoimmune diseases found were dominated by systemic lupus erythematosus, rheumatoid arthritis. Multiple studies found that systemic lupus erythematosus and rheumatoid arthritis were more prevalent in females than in males, these results parallel our findings [15, 34–36]. The females were more likely than the males to have the organ-specific autoimmune diseases. Type 1 diabetes and Graves’disease were the commonest of organ-specific autoimmune diseases. Males were 2.89 times more likely to develop the type 1 diabetes than females in our study, consistent with some previous studies [37, 38]. In contrast, Wändell et al. report no significant sex difference in type 1 diabetic in children 0–14 years of age [37]. This discrepancy may be explained by methodological approach notably the study population is stratified by age group in this study, but not our studies [37].

In our study, there were no cases of monogenic autoinflammatory diseases in our study. The males were 2.04 times more likely than the females to have polygenic autoinflammatory diseases. Furthermore, males were 3.19 times more to develop systemic polygenic autoinflammatory diseases than females, although this increase was not statistically significative. These systemic polygenic autoinflammatory diseases were dominated by systemic non autoimmune vascularitis. Several epidemiological data found that some systemic non autoimmune vascularitis such giant cell arteritis are more likely frequent in females than in males [39, 40]. However, in our study, males were likely to have had the giant cell arteritis compared to females. These differences may reflect the participant inclusion criteria, and the site of study, which were hospital monocentric with exhaustive recruitment of all autoimmune and autoinflammatory cases in our study.

Organ-specific polygenic autoinflammatory diseases were more common in females than in males. Among the organ-specific polygenic autoinflammatory diseases, gout as microcrystalline was the most prevalent. Males were 1.92 times more likely to have gout compare to females, as were found in this study [22].

Urban-rural based differences in autoimmune and autoinflammatory diseases

The systemic autoimmune diseases, in our study, were more prevalent in patients living in urban areas than in patients living in rural. There were no statistically significant differences between patients living in urban areas and patients living in rural areas in regards to systemic autoimmune diseases as systemic lupus erythematosus and rheumatoid arthritis, these results are not in line with findings from previous studies. Gergianaki et al. Showed that the risk of systemic lupus erythematosus in urban was 2.08 times more than in rural areas [41]. Then, Iltchev P et al. found that the rheumatoid arthritis was more than twice as many in urban areas than in rural areas [42]. Both studies were population-based study with high sample size, ours was hospital-based study, which may explain this contrast.

The patients living in urban were more likely than the patients living in rural areas to have the organ-specific autoimmune diseases. The patients living in urban areas were not more likely to have had type 1 diabetes and Graves’disease, compared to patients living in rural areas, in accordance with literature data [43, 44].

The patients living in urban areas were more likely than the patients living in rural areas to develop the polygenic autoinflammatory diseases. Systemic polygenic autoinflammatory diseases were dominated by systemic non autoimmune vascularitis among which the giant cell arteritis. This population-based study found that the giant cell arteritis was significantly more frequent in patients living in urban areas than the patients living in rural areas, consistent with our study findings [45].

Organ-specific polygenic autoinflammatory diseases were more frequent in patients living in urban areas than in patients living in rural areas. The organ-specific polygenic autoinflammatory diseases were dominated by the chronic inflammatory rheumatism including the gout as microcrystalline and the chronic inflammatory bowel disease. Dehlin et al. studied the incidence and prevalence of gout in Western Sweden in which there was no significant difference in the prevalence of gout in rural compared to urban areas, this is in concordance with our study findings [46].

Study limitations

Our study has limitations. Firstly, the patients followed as outpatients in the internal medicine department, and the patients treated in other departments at the University Hospital Center of the Point G and other health structures for autoimmune and autoinflammatory disease, which may have led to under-ascertainment on the latter. A second limitation, we had not confirmed the autoimmune and autoinflammatory disease in certain patients because of socio-economic status. Thus, the patients did not perform certain specific para-clinical examinations to confirm the diagnosis, which may cause confounding biases. Finally, the study was performed in localized areas, single-center study, which may hamper generalizability.

Study strengths

This study contains several strengths. First, it is a long-term observational study with exhaustive method of sampling of all cases of autoimmune and autoinflammatory diseases. Second, consent procedures were not required for enrollment, therefore minimizing bias and increasing slightly the generalizability of results. Third, our study demonstrates the scope of the problematic of age, urban-rural, gender and sex-based variations in autoimmune and autoinflammatory diseases. And finally, we believe that our data provide sufficient grounds for a reexamination of the correlation between the age-, urban-rural-, gender- and sex-specific determinants and the autoimmune and autoinflammatory diseases.

Perspectives

The Malian registry of autoimmune and autoinflammatory diseases should be more funded and structured in order to provide a large multi-center cohort study necessary to identify the significant correlations between the age group-, urban-rural-, gender- and sex-based differences, and also extended to ethnicity, seasonality, geographic, occupational variations in autoimmune and autoinflammatory diseases. In addition, it should permit to more explore its specific determinants associated to the development of these autoimmune diseases and autoinflammatory diseases.

Autoimmune diseases are significantly prevalent in young adult while autoinflammatory diseases in elderly. Gender related occupations are found among some professions such as houseworker, farmer, and worker. The systemic autoimmune diseases are more frequently diagnosed in females than in males. The females are more likely than the males to have the organ-specific autoimmune diseases. There are no cases of monogenic autoinflammatory diseases in our study. The males are more likely than the females to have polygenic autoinflammatory diseases. Furthermore, males are more likely to develop systemic polygenic autoinflammatory diseases than females. Organ-specific polygenic autoinflammatory diseases were more common in females than in males. The systemic autoimmune diseases are more prevalent in patients living in urban areas at the time of diagnosis than in patients living in rural. The patients living in urban are more likely than the patients living in rural areas to have the organ-specific autoimmune diseases. The patients living in urban areas are more likely than the patients living in rural areas to develop the polygenic autoinflammatory diseases. There were no statistically significant differences between patients living in urban areas and patients living in rural in regarding systemic polygenic autoinflammatory diseases Organ-specific polygenic autoinflammatory diseases were more frequent in patients living in urban areas than in patients living in rural areas. Upon studying the age-, urban-rural-, gender- and sex-based differences in autoimmune and autoinflammatory diseases, its specific determinants associated to the development of autoimmune and autoinflammatory diseases should be more explored.

As an ethics statement, given the nature of the study, formal ethical approval from an ethics committee was sought. The study was approved by the Research Ethics Committee of the Faculty of Medicine and Odontostomatology of Bamako. In addition, the formal permission to conduct this study was obtained from the General Director of University Hospital Center of the Point G.

Primary Funding Source:

Not applicable.

FUNDING

All authors declare that no grants for this research were received from any funding agency.

AVAILABILITY OF DATA AND MATERIALS

Data supporting the results for this study are provided as tables within the article and as supplementary materials.

ACKNOWLEDGMENTS

We express our sincere gratitude to the head nurses of the two units of our department of internal medicine who are responsible of medical records and registry of hospitalization, and all the healthcare providers who participated in this study.

AUTHORS' CONTRIBUTIONS

Conception: Kaly Keïta and Hamar Alassane Traoré. Design of the study: Kaly Keïta, Boua Daoud Camara, Alassane Alfousséni Doumbia, and Mahamadou Diakité. Data collection: Cheick Oumar Kamissoko, Nagou Tolo, Nanko Doumbia, Brehima Boly Berthé, Drissa Sangaré, Mahamadou Saliou and Kaly Keïta. Data analysis and interpretation: Ibrahima Amadou Dembélé, Mamadou Cissoko, Youssouf Fofana, Djibril Sy, Djénèbou Traoré, Assétou Soukho Kaya, Mamadou Dembélé, Abdoulaye Keïta, Abdoulaye Diawara and Hamar Alassane Traoré. Supervision: Mahamadou Diakité. Writing original draft: Kaly Keïta, Mamadou Wélé, Kassim Traoré , Jeffrey G. Shaffer. Writing review and editing: Kaly Keïta, Boua Daoud Camara, Alassane Alfousséni Doumbia, Cheick Oumar Kamissoko, Djibril Sy, Djénèbou Traoré, Assétou Soukho Kaya, Mamadou Dembélé, Abdoulaye Keïta, Abdoulaye Diawara, Mamadou Wélé, Kassim Traoré, Jeffrey G. Shaffer, Mahamadou Diakité and Hamar Alassane Traoré. Guarantor of the study: Hamar Alassane Traoré. All the authors have read and agreed to the final manuscript.

COMPETING INTERESTS

The authors declare that they have no competing interests.

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Table 1: Distribution of patients according to the age groups and the autoimmune and autoinflammatory diseases
Age group	Autoimmune diseases			Autoinflammatory diseases
Age group	n (%)	OR (95% CI)	p-value	n (%)	OR (95% CI)	p-value
< 19 years	47 (16.5)	1.38 (0.46 - 4.13)	0.560	5 (12,5)	0.72 (0.27 – 1,93)	0.509
20 - 39 years	153 (53.7)	5.02 (2.01 – 12.57)	0.000	8 (20,0)	0.21 (0.10 – 0.47)	0.000
40 - 59 years	61 (21.4)	0.70 (0.31 - 1.58)	0.385	11 (27,5)	1.40 (0.66 – 2.97)	0.377
60 - 79 years	24 (8.4)	0.13 (0.06 - 0.30)	0.000	16 (40,0)	8.13 (3.75 – 17.61)	0.000

Table 2: Distribution of patients according to the profession and the autoimmune and autoinflammatoty diseases
Profession	Autoimmune diseases		Autoinflammatory diseases
Profession	Autoimmune diseases, n (%)	Not autoimmune diseases, n (%)	Autoinflammatory diseases, n (%)	Not autoinflammatory diseases, n (%)
Houseworker	109 (92.4)	9 (7.6)	9 (7.6)	109 (89.8)
Pupil/Student	45 (91.8)	4 (8.2)	5 (10.2)	44 (89.8)
Trader	26 (92.9)	2 (7.1)	2 (7.1)	26 (92.9)
Farmer	19 (79.2)	5 (20.8)	6 (25.0)	18 (75.0)
Worker	12 (75.0)	4 (25.0)	5 (31.3)	11 (68.8)
Civil servant	32 (88.9)	4 (11.1)	6 (16.7)	30 (83.3)
Not employed	4 (100)	0 (0)	0 (0)	4 (100)
Others	2 (100)	0 (0)	0 (0)	2 (100)
No information	18 (94.7)	1 (5.3)	1 (5.3)	18 (94.7)
Artisan	14 (82.4)	3 (5.3)	5 (29.4)	12 (70.6)
Liberal profession	4 (100)	0 (0)	1 (25.0)	3 (75.0)

Table 3: Distribution of patients according to the sex and the autoimmune diseases
Autoimmune diseases		Sex				Male-to-female ratio		OR (95% CI)		p-value
		Male, n= 101 n (%)		Female, n= 206 n (%)
Systemic autoimmune diseases		7 (6.31)		63 (30.58)		0.11		0.15 (0.07 – 0.35)		0.000
Systemic lupus erythematosus		3 (2.70)		40 (19.42)		0.07		0.12 (0.03 – 0.38)		0.000
Systemic scleroderma		1 (0.90)		3 (1.46)		0.33		0.61 (0.18 – 5.98)		1.000
Dermato-polymyositis		0 (0.00)		1 (0.49)		0		-		1.000
Rheumatoid arthritis		3 (2.70)		13 (6.31)		0.23		0.41 (0.12 – 1.48)		0.162
Sharp syndrome/mixte connective tissue diseases^a		0 (0.00)		6 (2.91)		0		-		0.095
	Rheumatoid arthritis + Systemic Lupus erythematosus	0 (0.00)		1 (0.49)		0		-		0.529
	Rheumatoid arthritis + Systemic Lupus erythematosus + Dermato-polymyositis + Systemic Scleroderma	0 (0.00)		1 (0.49)		0		-
	Systemic Lupus erythematosus + Systemic Scleroderma	0 (0.00)		4 (1.94)		0		-
Systemic auto-immune vascularitis		0 (0.00)		0 (0.00)		-		-		-
Organ-specific autoimmune diseases			90 (81.08)		131 (63.59)		0.69		2.45 (1.41– 4.27)	0.001
Type 1 diabete			64 (57.66)		77 (37.38)		0.83		2.28 (1.43 – 3.65)	0.001
Autoimmune polyendocrinpathies^a			1 (0.90)		1 (0.49)		1		1.86 (0.12 – 30.08)	1.000
De Quervain’s thyroiditis			0 (0.00)		1 (0.49)		0		-	1.000
Graves’disease			10 (9.01)		38 (18.45)		0.26		0.44 (0.20 – 0.92)	0.025
Guillain Barre syndrome			4 (3.60)		3 (1.46)		1.33		2.55 (0.56 – 11.62)	0.245
Multiple sclerosis			0 (0.00)		1 (0.49)		0		-	1.000
Myasthenia gravis			3 (2.70)		0 (0.00)		-		-	0.042
Autoimmune hepatitis			1 (0.90)		0 (0.00)		-		-	0.350
Autoimmune hemolytic anemia			2 (1.80)		8 (3.88)		0.25		0.45 (0.09 – 2.17)	0.499
Immunological thrombocytopenic prupura			0 (0.00)		1 (0.49)		0		-	1.000
Biermers’disease			6 (5.41)		2 (0.97)		3		5.82 (1.56 – 29.38)	0.024

Autoimmune polyendocrinpathies^a: Graves’disease + Addison’s diseases (2 cases)

Table 4: Distribution of patients according to diseases the sex and the autoinflammatory
Autoinflammatory diseases			Sex				Male-to-female ratio		OR (95% CI)	p-value
			Male, n= 101 n (%)		Female, n= 206 n (%)
Monogenic autoinflammatory diseases			0 (0.00)		0 (0.00)		-		-	-
Polygenic autoinflammatory diseases			20 (18.02)		20 (9.71)		1		2.04 (4.52 – 3.99)	0.033
Systemic polygenic autoinflammatory diseases			5 (4.50)		3 (1.46)		1.66		3.19 (0.75 – 13.61)	0.134
Systemic non autoimmune vascularitis			5 (4.50)		1 (0.49)		5		9.67 (1.12 – 83.83)	0.021
	Horton’s disease		2 (1.80)		0 (0.00)		-		-	0.122
	Periartritis nodosa		1 (0.90)		0 (0.00)		-		-	0.350
	Vascularitis of undetermined origin		0 (0.00)		1 (0.49)		0		-	O.650
	Burger angitis		1 (0.90)		0 (0.00)		-		-	0.350
	Other systemic non autoimmune vascularitis		2 (1.80)		0 (0.00)		2		-	0.122
		Burger angitis	1 (0.90)		0 (0.00)		-		-	0.122
		leukocytoclassical vascularitis	1 (0.90)		0 (0.00)		-		-
Systemic sarcoidosis			0 (0.00)		1 (0.49)		0		-	1.000
Still’s disease			0 (0.00)		1 (0.49)		0		-	1.000
Organ-specific polygenic autoinflammatory diseases				15 (13.31)		17 (8.25)		0.88	1.74 (0.83 – 3.63)	0.138
*Chronic inflammatory rheumatism*				*11 (9.91)*		*11 (5.34)*		1	*1.95 (0.82 – 4.65)*	*0.127*
Pseudo rheumatoid arthritis				1(0.90)		0 (0.00)		-	-	0.350
Microcrystalline arthropathies				8 (7.21)		8 (3.88)		1	1.92 (0.70 – 5.27)	0.197
	Gout			8 (7.21)		8 (3.88)		1	1.92 (0.70 – 5.27)	0.197
	Chondrocalcinosis			0(0.00)		0(0.00)		-	-	-
Spondylarthropathies				2(1.80)		1(0.49)		2	3.76 (0.34 – 41.95)	0.281
	Reactive arthritis			1(0.90)		0(0.00)		-	-	0.281
	Psoriatic rheumatism			0(0.00)		1(0.49)		0	-
	Ankiylosing spondylitis			1(0.90)		0(0.00)		-	-
Others chronic inflammatory diseases				2(1.80)		0(0.00)		-	-	0.543
	Juvenile idiopathic arthritis			0(0.00)		1(0.49)		0	-	1.000
	Jaccoub’s arthropathy			0(0.00)		1(0.49)		0	-
*Chronic inflammatory bowel disease*				*4 (3.60)*		*6 (2.91)*		*0.67*	*1.25 (0.34 – 4.51)*	*0.000*
	Crohn’s diseases			1(0.90)		1(0.49)		1	1.85 (0.12 – 30.08)	1.000
	Ulcerative colitis			3 (2.70)		5 (2.43)		0.67	1.12 (0.26 – 4.76)	1.000

Table 5: Distribution of patients according to the residency and the autoimmune diseases
Autoimmune diseases	Residency				OR (95% CI)		p-value
	Urban, n= 214 n (%)		Rural, n= 103 n (%)
*Systemic autoimmune diseases*	*44 (20.56)*		*26 (25.24)*		*0.77 (0.44 – 1.33)*		*0.347*
Systemic lupus erythematosus	28 (13.08)		15 (14.56)		0.88 (0.44 – 1.74)		0.719
Systemic scleroderma	1 (0.47)		3 (2.91)		0.16 (0.02 – 1.52)		0.102
Dermato-polymyositis	0 (0.00)		1 (0.97)		-		0.325
Rheumatoid arthritis	11 (5.14)		5 (4.85)		1.06 (0.36 – 3.14)		0.913
Sharp syndrome/mixte connectivitis tissue diseases^a	5 (2.34)		1(0.97)		2.44 (0.28 – 21.16)		0.366
Systemic auto-immune vascularitis	0 (0.00)		0 (0.00)		-		-
Organ-specific autoimmune diseases		153 (71.50)		68 (66.02)		1.29 (0.78 – 2.14)	0.320
Type 1 diabete		101 (47.20)		40 (38.83)		1.41 (0.87 – 2.27)	0.161
Autoimmune polyendocrinpathies^b		1 (0.47)		1(0.97)		0.48 (0.03 – 7.73)	0.545
De Quervain’s thyroiditis		1 (0.47)		0(0.00)		-	1.000
Graves’disease		35 (16.36)		23 (12.62)		1.35 (0.75 – 2.69)	0.385
Guillain Barre syndrome		5 (2.34)		2 (1.94)		1.21 (0.23 – 6.33)	1.000
Multiple sclerosis		1 (0.47)		0(0.00)		-	1.000
Myasthenia gravis		1 (0.47)		2(1.94)		0.24 (0.02 – 2.65)	0.247
Autoimmune hepatitis		1 (0.47)		0(0.00)		-	1.000
Autoimmune hemolytic anemia		4 (1.87)		6 (5.83)		0.31 (0.08 – 112)	0.123
Immunological thrombocytopenic prupura		0 (0.00)		1(0.97)		-	0.325
Biermers’disease		5 (2.34)		3 (2.91)		0.80 (0.19 – 3.40)	0.718

Sharp syndrome/mixte connective tissue diseases^a: Systemic Lupus erythematosus + Rheumatoid arthritis (1 case); Systemic Lupus erythematosus + Rheumatoid arthritis + Dermato-polymyositis (DPM) + systemic scleroderma (1case); Systemic Lupus erythematosus + systemic scleroderma (4case)

Autoimmune polyendocrinpathies^b: Graves’disease + Addison’s diseases (2 cases)

Table 6: Distribution of patients according to the residency and the autoinflammatory diseases
Autoinflammatory diseases			Residency		OR (95% CI)	p-value
Autoinflammatory diseases			Urban, n= 214 n (%)	Rural, n= 103 n (%)	OR (95% CI)	p-value
Monogenic autoinflammatory diseases			0 (0.00)	0 (0.00)	-	-
Polygenic autoinflammatory diseases			25 (11.68)	15 (14.56)	0.78 (0.39 – 1.54)	0.469
Systemic polygenic autoinflammatory diseases			4 (1.87)	4 (3.88)	0.47 (0.12 – 1.92)	0.281
Systemic non autoimmune vascularitis			3 (1.40)	3 (2.91)	0.47 (0.09 – 2.39)	0.394
	Horton’s disease		2 (0.93)	0 (0.00)	-	1.000
	Periartritis nodosa		0 (0.00)	1 (0.97)	-	0.325
	Vascularitis of undetermined origin		0 (0.00)	1 (0.97)	-	0.325
	Other systemic non autoimmune vascularitis		1 (0.47)	1 (0.97)	0.48 (0.03 – 7.73)	0.545
		Burger angitis	0 (0.00)	1 (0.97)	-	-
		Leucytoclassic vascularitis	1 (0.47)	0 (0.00)	-	-
Systemic sarcoidosis			1 (0.47)	0 (0.00)	-	1.000
Still’s disease			0 (0.00)	1 (0.97)	-	0.325
Organ-specific polygenic autoinflammatory diseases			21 (9.81)	11 (10.68)	0.91 (0.42 – 1.97)	0.810
*Chronic inflammatory rheumatism*			*16 (7.48)*	*6 (5.83)*	*1.31 (0.50 – 3.44)*	*0.588*
Pseudo rheumatoid arthritis			1 (0.47)	0 (0.00)	-	1.000
Microcrystalline arthropathies			11 (5.14)	5 (4.85)	1.06 (0.36 – 3.14)	0.913
	Gout		11 (5.14)	5 (4.85)	1.06 (0.36 – 3.14)	0.913
	Chondrocalcinosis		0 (0.00)	0 (0.00)	-	-
Spondylarthropathies			2 (0.93)	1 (0.97)	0.96 (0.86 –10.74)	1.000
	Reactive arthritis		0 (0.00)	1 (0.97)	-	0.694
	Psoriatic rheumatism		1 (0.47)	0 (0.00)	-
	Ankiylosing spondylitis		1 (0.47)	0 (0.00)	-
Others chronic inflammatory diseases			2 (0.93)	0 (0.00)	-	1.000
	Juvenile idiopathic arthritis		1 (0.47)	0 (0.00)	-	1.000
	Jaccoub’s arthropathy		1 (0.47)	0 (0.00)	-	1.000
*Chronic inflammatory bowel disease*			*5 (2.34)*	*5 (4.85)*	*0.47 (0.13 – 1.66)*	*0.391*
	Crohn’s diseases		1 (0.47)	1 (0.97)	0.48 (0.03 – 7.73)	0.545
	Ulcerative colitis		4 (1.87)	4 (3.88)	0.47 (0.12 - 1.92)	0.281

The authors declare no competing interests.

FigureS1.png
Distribution of patients according to the sociodemographic data such the sex (A), the age groups (B), the residency (C), and the profession (D)
FigureS2.png
Distribution of autoimmune and autoinflammatory diseases related patients according to the sex and the profession

Age, Urban-Rural, Gender and Sex-Based Differences in Autoimmune and Autoinflammatory Diseases: A Cross-Sectional Study

Status:

Version 1

Abstract

INTRODUCTION

METHODS