Epidemiology and Causation

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Overview

Wingerchuk, 2011). Findings published in the journal Neurology (Wallin, et al., 2019) on Feb. 15, 2019, estimate the 2017 prevalence of adults with MS in the United States to be 362 cases per 100,000, or 913,925. In addition, the study supports previous evidence of a 3:1 female to male ratio.MS is more common in areas inhabited by people of northern European ancestry. It is more common in Europe, the United States, Canada, New Zealand, and some parts of Australia; it is much less common in Asia and rare in tropical and sub-tropical regions (Ascherio & Munger, 2016). With some notable exceptions, the global distribution of MS increases with distance north or south of the equator, although there is some evidence that the north-south incidence gradient may have disappeared in the northern hemisphere (Koch-Henriksen & Sorensen, 2011).MS is an immune-mediated disorder and is thought by most to be autoimmune, though the specific antigen(s) have not yet been identified. The cause of MS involves both genetic and environmental factors." c-nmssatomrichtext_nmssatomrichtext-host="">

Multiple sclerosis is an inflammatory demyelinating disease that most often appears in young adulthood, with the incidence peaking around age 30 (Wingerchuk, 2011). Findings published in the journal Neurology (Wallin, et al., 2019) on Feb. 15, 2019, estimate the 2017 prevalence of adults with MS in the United States to be 362 cases per 100,000, or 913,925. In addition, the study supports previous evidence of a 3:1 female to male ratio.MS is more common in areas inhabited by people of northern European ancestry. It is more common in Europe, the United States, Canada, New Zealand, and some parts of Australia; it is much less common in Asia and rare in tropical and sub-tropical regions (Ascherio & Munger, 2016). With some notable exceptions, the global distribution of MS increases with distance north or south of the equator, although there is some evidence that the north-south incidence gradient may have disappeared in the northern hemisphere (Koch-Henriksen & Sorensen, 2011).MS is an immune-mediated disorder and is thought by most to be autoimmune, though the specific antigen(s) have not yet been identified. The cause of MS involves both genetic and environmental factors.

chart depicting MS prevalence increase over 5 decades, per 10,000 U.S. residents

Interaction of Genetics and the Environment

International MS Genetics Consortium (IMSGC) has confirmed that MS risk is governed by 233 human genomic variations in the largest MS genetics study to date (Patsopoulos et al., 2019). Though genetic variants alone are insufficient to predict who will develop MS, this information combined with a better understanding of environmental risk factors may one day help predict an individual’s risk of developing MS.An array of environmental risk factors for MS have been examined over the past century. Of those, the Epstein-Barr virus (EBV), ultra-violet light exposure and vitamin D levels, cigarette smoking (Wingerchuk, 2011) and obesity (Ascherio & Munger, 2016) have the clearest supporting evidence In their 2015 review of environmental risk factors from the perspective of timing in adult-onset MS, Mouhieddine et al. (2015) suggest that vitamin D influences risk of developing MS, that EBV acts during adolescence or early adulthood and smoking increases a person’s susceptibility to MS." c-nmssatomrichtext_nmssatomrichtext-host="">

The International MS Genetics Consortium (IMSGC) has confirmed that MS risk is governed by 233 human genomic variations in the largest MS genetics study to date (Patsopoulos et al., 2019). Though genetic variants alone are insufficient to predict who will develop MS, this information combined with a better understanding of environmental risk factors may one day help predict an individual’s risk of developing MS.An array of environmental risk factors for MS have been examined over the past century. Of those, the Epstein-Barr virus (EBV), ultra-violet light exposure and vitamin D levels, cigarette smoking (Wingerchuk, 2011) and obesity (Ascherio & Munger, 2016) have the clearest supporting evidence In their 2015 review of environmental risk factors from the perspective of timing in adult-onset MS, Mouhieddine et al. (2015) suggest that vitamin D influences risk of developing MS, that EBV acts during adolescence or early adulthood and smoking increases a person’s susceptibility to MS.

The Role of Genetics in MS

Compston & Coles, 2008):

The risk of developing MS in the general population is approximately 0.1%.
The risk for a child with one parent who has MS is approximately 2%.
The risk for a child with two parents who have MS is approximately 12.2% (Ebers et al, 2000).
The risk for a dizygotic twin and other siblings is approximately 5%.
The risk for monozygotic twins is approximately 25% (Willer et al, 2003).
The risk for second-degree and third-degree relatives is approximately 1%.

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As the role of genetics in MS continues to be explored, the following statements can be used to help frame conversations with patients about MS risk (Compston & Coles, 2008):

The risk of developing MS in the general population is approximately 0.1%.
The risk for a child with one parent who has MS is approximately 2%.
The risk for a child with two parents who have MS is approximately 12.2% (Ebers et al, 2000).
The risk for a dizygotic twin and other siblings is approximately 5%.
The risk for monozygotic twins is approximately 25% (Willer et al, 2003).
The risk for second-degree and third-degree relatives is approximately 1%.

Compston & Coles, 2008):

The risk of developing MS in the general population is approximately 0.1%.
The risk for a child with one parent who has MS is approximately 2%.
The risk for a child with two parents who have MS is approximately 12.2% (Ebers et al, 2000).
The risk for a dizygotic twin and other siblings is approximately 5%.
The risk for monozygotic twins is approximately 25% (Willer et al, 2003).
The risk for second-degree and third-degree relatives is approximately 1%.

" c-nmssatomrichtext_nmssatomrichtext-host="">

As the role of genetics in MS continues to be explored, the following statements can be used to help frame conversations with patients about MS risk (Compston & Coles, 2008):

The risk of developing MS in the general population is approximately 0.1%.
The risk for a child with one parent who has MS is approximately 2%.
The risk for a child with two parents who have MS is approximately 12.2% (Ebers et al, 2000).
The risk for a dizygotic twin and other siblings is approximately 5%.
The risk for monozygotic twins is approximately 25% (Willer et al, 2003).
The risk for second-degree and third-degree relatives is approximately 1%.

MS Interethnic/Interracial Group Variability

Wallin et al., 2012; Langer-Gould et al., 2013).In the largest genetic study of people with MS of non-European ancestry, investigators obtained DNA samples from 1,162 Blacks with MS and 2,092 Blacks without MS, as well as 577 Whites with MS and 461 Whites without MS (Isobe et al., 2013). The team looked for similarities and differences in 128 gene variants that have been associated with MS. They confirmed associations of key immune-response genes (HLA) with MS among African Americans. However, among 73 non-HLA genes that were associated with MS among White Americans, only 8 were associated with MS among African Americans. The authors concluded that MS genetic risk in African Americans only partially overlaps with that of Europeans and could explain the difference of MS prevalence between populations.Conversations about the genetic contribution to MS risk should include mention of the complex interaction with environmental factors. Increased incident rates of MS and generally worse prognosis in African Americans suggest social, environmental and genetic risk factors that impact disease (Amezcua & McCauley, 2020)." c-nmssatomrichtext_nmssatomrichtext-host="">

Research has demonstrated that MS occurs in most racial and ethnic groups, including Blacks, Asians and Hispanics/Latinos/Latinx. Susceptibility rates vary among these groups, with findings suggesting that Black women have a higher than previously reported risk of developing MS (Wallin et al., 2012; Langer-Gould et al., 2013).In the largest genetic study of people with MS of non-European ancestry, investigators obtained DNA samples from 1,162 Blacks with MS and 2,092 Blacks without MS, as well as 577 Whites with MS and 461 Whites without MS (Isobe et al., 2013). The team looked for similarities and differences in 128 gene variants that have been associated with MS. They confirmed associations of key immune-response genes (HLA) with MS among African Americans. However, among 73 non-HLA genes that were associated with MS among White Americans, only 8 were associated with MS among African Americans. The authors concluded that MS genetic risk in African Americans only partially overlaps with that of Europeans and could explain the difference of MS prevalence between populations.Conversations about the genetic contribution to MS risk should include mention of the complex interaction with environmental factors. Increased incident rates of MS and generally worse prognosis in African Americans suggest social, environmental and genetic risk factors that impact disease (Amezcua & McCauley, 2020).

Epstein-Barr Virus

Thacker et al, 2006). Elevated serum antibody titers to EBV nuclear antigen 1(EBNA-1) precede the clinical onset of MS (Ascherio & Munger, 2016). The strongest epidemiological evidence to date that EBV may be causally related to MS showed that MS occurs only after a primary EBV infection (Levin et al., Ann Neurol 2010). In established MS, EBV antibody titers have been associated with MRI activity in some (Farrell et al, 2009) but not all studies. Some studies have also found evidence of EBV infection in MS lesions, (Serafini et al, 2007), but this observation has not been reliably replicated.The evidence concerning the relationship between MS and EBV is not conclusive. (Willis et al, 2009; Peferoen et al, 2010; Sargsyan et al, 2010). There are arguments for (Pakpoor & Ramagopalan, 2013) and against (Salzer & Myhr, 2013) EBV as a requisite causative agent in MS pathogenesis." c-nmssatomrichtext_nmssatomrichtext-host="">

A history of symptomatic infectious mononucleosis increases MS risk more than twofold (Thacker et al, 2006). Elevated serum antibody titers to EBV nuclear antigen 1(EBNA-1) precede the clinical onset of MS (Ascherio & Munger, 2016). The strongest epidemiological evidence to date that EBV may be causally related to MS showed that MS occurs only after a primary EBV infection (Levin et al., Ann Neurol 2010). In established MS, EBV antibody titers have been associated with MRI activity in some (Farrell et al, 2009) but not all studies. Some studies have also found evidence of EBV infection in MS lesions, (Serafini et al, 2007), but this observation has not been reliably replicated.The evidence concerning the relationship between MS and EBV is not conclusive. (Willis et al, 2009; Peferoen et al, 2010; Sargsyan et al, 2010). There are arguments for (Pakpoor & Ramagopalan, 2013) and against (Salzer & Myhr, 2013) EBV as a requisite causative agent in MS pathogenesis.

Vitamin D

Munger et al., 2006; Salzer et al., 2012) and 25(OH)D deficiency has been associated with an increased risk of MS (Munger et al., 2017). Genetically determined low 25(OH)D has been associated with an increased risk of both adult and pediatric onset of MS. (Mokry et al., 2015; Rhead et al., 2016; Gianfrancesco et al., 2017)In a one-year, double blind, randomized, placebo-controlled study looking at the safety and efficacy of vitamin D3 as an add on therapy to interferon β-1b (IFNB), vitamin D3 reduced MRI disease activity (Soilu-Hӓnninen et al., 2012). Results from the Betaferon/Betaseron in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) and the Betaferon/Betaseron Efficacy Yielding Outcomes of a New Dose in multiple sclerosis (BEYOND) studies suggest higher 25(OH)D level may have a positive effect on clinical and MRI measures (Ascherio & Munger, 2014; Fitzgerald et al., 2015). Randomized controlled clinical trials of high dose vitamin D also suggest a beneficial effect of vitamin D on MRI outcomes among patients on IFNB-1a therapy (Hupperts et al., 2019; Camu et al., 2019)." c-nmssatomrichtext_nmssatomrichtext-host="">

Evidence pointing to a critical role for vitamin D includes that high levels of serum 25(OH)D prior to MS clinical onset is associated with a reduced risk of MS (Munger et al., 2006; Salzer et al., 2012) and 25(OH)D deficiency has been associated with an increased risk of MS (Munger et al., 2017). Genetically determined low 25(OH)D has been associated with an increased risk of both adult and pediatric onset of MS. (Mokry et al., 2015; Rhead et al., 2016; Gianfrancesco et al., 2017)In a one-year, double blind, randomized, placebo-controlled study looking at the safety and efficacy of vitamin D3 as an add on therapy to interferon β-1b (IFNB), vitamin D3 reduced MRI disease activity (Soilu-Hӓnninen et al., 2012). Results from the Betaferon/Betaseron in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) and the Betaferon/Betaseron Efficacy Yielding Outcomes of a New Dose in multiple sclerosis (BEYOND) studies suggest higher 25(OH)D level may have a positive effect on clinical and MRI measures (Ascherio & Munger, 2014; Fitzgerald et al., 2015). Randomized controlled clinical trials of high dose vitamin D also suggest a beneficial effect of vitamin D on MRI outcomes among patients on IFNB-1a therapy (Hupperts et al., 2019; Camu et al., 2019).

Factores epidemiológicos y causas

Overview

Interaction of Genetics and the Environment

The Role of Genetics in MS

MS Interethnic/Interracial Group Variability

Epstein-Barr Virus

Vitamin D

Smoking

Obesity