Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system that may cause neurological dysfunction in young adults (1–3). It has been reported that MS ranked the 10th leading cause of disease burden (4). Previous studies have shown that MS has a genetic susceptibility and is also associated with several environmental risk factors including Epstein-Barr virus infection, vitamin D insufficiency, smoking, and childhood obesity (5–8). However, the exact etiology of the disease is still not fully understood.

The distribution of MS varies substantially among regions. Studies have shown that Western Europe and North America have the highest prevalence, followed by Central and Eastern Europe, the Balkans, Australia, and New Zealand, while Asia, Africa, and the Middle East have the lowest prevalence (9, 10). During the past decades, previous studies have reported the increasing incidence and prevalence of MS globally (9–13). More importantly, the significantly increasing trend of MS incidence and prevalence was observed in regions considered low-prevalence areas such as India (14), Latin America (15, 16), Iran (10, 17), Japan (18), the Greater Hobart cohort of Tasmania, and Australia (19).

Over recent decades, there have been changes in the risk factors of MS contributing to the increase in MS incidence and prevalence. Previously, significant period and cohort effects have been reported for the increasing female incidence in Danish and Swiss populations (20, 21). However, evidence regarding the interactions between the effects of age, period, and cohort in MS globally is limited. Age-period-cohort (APC) analysis is an important model to investigate how and why disease trends change over time. It is a tool for interpreting temporal variables in epidemiological rates (22). The age effect represents the variations in different age groups. Period effects reflect changes over the period that affect people of all age groups simultaneously. Cohort effects are the discriminations between early and later birth cohort groups that experience the same initial exposure environment (23).

Previously, by using the 2016 GBD data, the global and regional MS burden has been reported (23). However, an assessment of the global MS disease burden, trends, and age-period-cohort effects based on the new estimates from GBD 2019 has not been done. In the current study, we aimed to demonstrate the global and regional temporal trends in MS incidence, deaths, and disability-adjusted life years from 1990 to 2019. We further investigated the effects of age, period, and cohort by using the age-period-cohort analysis.

In the current study, we evaluated the most recent examination of the global, regional, and national burden and temporal trends in MS by using the age–period–cohort analysis. From 1990 to 2019, we found that the global number of incidences, deaths, and DALYs of MS increased while the ASR decreased. The incidence rate remained relatively stable, whereas death and DALYs rates increased somewhat. Regions and countries with a higher SDI had a greater number and ASR of incidence, death, and DALYs. High-income North America and Western Europe were the top two regions with the highest ASIRs, ASDRs, and age-standardized DALYs. The age effect showed that the RRs of incidence and DALYs reached the peak at ages 30–39 and 50–59, respectively. The period effect showed that the RRs of deaths and DALYs increased with the period. The cohort effect showed that the later cohort has lower RRs of deaths and DALYs than the early cohort.

Previous studies have shown a relatively stable or slightly increasing incidence rate of MS in whites over the past four or five decades (32, 33). Our data from GBD 2019 showed that the number of incidences is increasing globally, however, the rate is flat or mildly decreasing. The combined estimate of the total MS incidence in 75 countries was 2.1 (95% CI, 2.09–2.12) per 100,000 persons/year (12), which differs from our estimate of 0.7 (95% UI, 0.6–0.8) per 100,000 persons in 2019. The lack of incidence data in some regions contributes to the discrepancy in global estimates of total incidence. We found that DALYs of MS made up 1.30% of all neurological disorders in 2019. Although the burden of MS is less than other neurological disorders such as headache disorders, Alzheimer's disease, and other dementias, the early age of MS onset and the significant impact on life quality and productivity cause a considerable non-fatal burden (11). The decreasing burden of MS, idiopathic epilepsy, and motor neuron disease observed since 1990 is partly in line with a rapidly improving quality of care, whereas an increasing burden of Parkinson's disease, Alzheimer's disease, and other dementias, which reflects increasing longevity and declining birth rates (34, 35). Several previous studies have reported a much higher crude death rate and ASDR in people with MS compared with the general population (36–38).

A positive correlation between age-standardized DALYs and SDI has been reported previously by using the GBD 2016 data (11). In agreement with the previous studies, we also detected a similar positive association between age-standardized DALY and SDI. Moreover, we found that ASIR and age-standardized DALYs in the high-medium SDI region declined significantly from 1990 to 2019 and the general improvement of clinical care and the abundance of medical resources in the regions may be the underlying causes. Our study found that ASIR from 1990 to 2019 in high SDI regions was the highest and that ASIR was moderately correlated with SDI levels, which confirmed that developed countries have a higher incidence of MS than developing countries (39). In high SDI regions, patients with MS are more likely to be treated and reported due to the availability of a robust healthcare system and adequate healthcare resources. Whereas, in low SDI regions, medical resources are so scarce that mild MS may go undetected. The significant ASIR in high SDI regions may account for its high DALYs rates. At the same time, the overall burden of MS may be much heavier than we estimated, given that data collection is limited to areas with underdeveloped health systems. The reason for the increased incidence trend of MS in most SDI regions may be that the immune system has undergone inappropriate changes over the past few decades in developed countries through the increasing use of healthy vaccinations and antibiotics, leaving people more vulnerable to autoimmune diseases (40).

Our results are consistent with some previous reports on the burden of MS in various regions (10, 11). The Atlas of MS has shown that Europe has the highest incidence, followed by the United States; South-Central Asia and Africa have the lowest incidence (12). An analysis of data from the Danish Multiple Sclerosis Registry showed that the incidence doubled in women between 1950 and 2009, while the increase in men was more modest. In contrast, the excess death rate among MS patients in Denmark has declined since 1950 (41). The incidence has been rising sharply in Iran between 1990 and 2017, possibly due to the growth of urbanization, which leads to changes in lifestyle, exposure to more weather pollutants, more stress, and consumption of fast food. DALYs are lower in the Middle East and Northern Africa, possibly due to the more benign course of MS disease (10). On the other hand, a study by Mansouri et al. indicated Latin America and the Caribbean showed increasing trends of incidence in recent years. Lack of vitamin D intake and genetic risk factors have been cited as the possible causes of this increasing trend (40).

Discrepancies in MS burden were also found across different age groups and genders. From 1990 to 2019, across all age groups, women had higher ASIR, ASDR, and ASR of DALYs due to MS. This result was consistent with those of previous studies carried out in Italy (42), Denmark (41), France (43), Australia (19, 44), and Norway (45), which similarly showed an increase in female incidence rates (46, 47). Gonadal hormones, lifestyle changes, lactation patterns, oral contraceptives, reduced physical activity, and increased stress may be the basis of this phenomenon (11, 47). Moreover, we found an earlier onset age for women in 2019 compared to 1990, indicating that more effort should be invested in women to combat MS.

There is an evident age effect on MS incidence and mortality as expected. Age effects explain the variation of indicators of interest in disease with age and reflect the nature of age changes (23, 48). The global high-risk age group for MS is 30–39 years old, which shows a similar age at MS onset patterns in published MS literature (9, 43, 49). Several countries, such as Kuwait (49), Newcastle, and Australia (44), show an age-specific bimodal distribution at MS onset during 1986–2011, indicating the existence of at least two age population segments at risk for MS. MS develops during the prime of life, and with the increasing aging of the global population (50), the burden on people living with MS will increase further, and the cost to society may soar in future. This finding broadly supports the previous study in this area that DALYs of MS globally peaked in the sixth decade (11). Higher life expectancy and early onset age have resulted in a high number of DALYs.

Although the global period effect and cohort effect of MS incidence have not been reported, the period effect and cohort effect have been evaluated in different regions previously. The period effect and cohort effect showed no significant change in the incidence of MS globally among the RRs of the different period groups and the same results showed in Lorraine, France between 1996 and 2015 (43), implying that genetic and environmental factors (5–8) that influence the disease's risk have not changed significantly or that factors that mitigate the disease's onset have emerged that have not yet been detected. On the other hand, Denmark and Kuwait show a significant period effect and cohort effect in incidence (41, 49). Moreover, a study in Norway found that the period effect on mortality was stable in men in the last three decades but increased for women (45). However, the period effect of mortality in Spain is decreasing from 1951 to 1997, probably due to an increasing life expectancy, while the risk of the birth cohort showed an increasing trend (51). A cohort effect analysis of MS-related mortality in North America and several European countries also showed a decline after the 1910–1930 generations (52). In the current study, the period effect showed that the RRs of deaths and DALYs increased with the period. The cohort effect showed that the later cohort has lower RRs of deaths and DALYs than the early cohort. Over the birth cohorts covered in our dataset, changes in lifestyle and environmental factors may have changed the risk of one cohort group over another. The late birth cohort, in comparison to the early birth cohort, received greater education, had a higher degree of awareness about health and illness prevention, and was more actively involved in treatment (22, 53). Furthermore, increasing risk factors for MS were discovered over time, raising public awareness of the disease. In APC analyses, birth cohort effects were largely unaffected by period effects due to changes in diagnostic criteria. In general, such changes are more likely too vague underlying birth cohort patterns than to emerge by chance (54).

One limitation of our current study is that the accuracy of our findings depends on the integrity and reliability of the GBD. However, insufficient diagnosis of diseases due to limited medical care in less developed regions and few national incidence and prevalence studies in high-income countries have led to the lack of partial data on the GBD, which in turn has resulted in biased models for predicting rates. In addition, the disease prediction models used in the database lack robust covariates for a more reliable risk assessment of the population (11). A second major limitation is that models are based on superimposed assumptions of age, period, and cohort effects. This not only creates identification problems but also led to a poor approximation of how social change occurs. Therefore, additional new models and methods are needed to test other theories of social change (23).

In conclusion, the cases of incidence, deaths, and DALYs of MS globally have all increased, whereas ASR has declined, with different trends in different regions. High SDI regions have a substantial burden of MS. Furthermore, we found significant age effects for incidence, deaths, and DALYs of MS globally, and period effects and cohort effects for deaths and DALYs. Health promotion, disease prevention, and rehabilitation should all receive significant attention, especially in high-risk areas.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.

ZQ: study design and manuscript drafting. YL: data collection, data analysis, and drawing graphs. KZ, YD, SY, BC, HW, and JJ: data collection and data analysis. KQ, ZG, and MZ: study design, data analysis, results interpretation, and manuscript reviewing. All authors contributed to the review of manuscript and the final version of paper.