By Ruth Ann Marrie, MD, PhD, FRCPC, FCAHS
Waugh Family Chair in Multiple Sclerosis, Professor of Medicine & Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba and Director, Multiple Sclerosis Clinic, Winnipeg, Manitoba, Canada.
The diseases and disorders known to coexist with multiple sclerosis (MS), overall, are not passive bystanders. While they have not been proven to cause MS – or vice versa – some of these comorbidities advance MS disease at a quicker pace; some may lead to an earlier death; and others could be, and should be, considered relevant harbingers of a diagnosis to come.
These comorbidities are not isolated to 1 organ system, but rather have been found in the endocrine, cardiovascular, respiratory, central nervous, and immune systems. The more comorbidities someone has, the higher the frequency of relapses in those with relapsing MS, the most common type of MS.1
Temporally speaking, the comorbidities can precede MS diagnosis or develop after diagnosis; they tend to increase in number with age and over time. As for their connection to MS, the very common denominator among many of these comorbidities is their inflammatory characteristic.
There are compelling reasons for specialists – endocrinologists, cardiologists, pulmonologists –and generalists, like primary care physicians, to appreciate the complexities of this disease, both in its prodromal state and beyond.
The literature shows how difficult diagnosis can be. A 2016 study of 4 MS centers found that 110 patients, 33% of the population, had been misdiagnosed for 10 years; their migraines had been misdiagnosed as MS.2 Then again, migraine and MS frequently overlap; a 2012 study reported that 43% of patients with MS also have migraine.3 Considering that females present with relapsing-remitting MS more often than males and deal more with migraines, this observation should not be a big surprise.
Patients come with histories including medical, familial, and lifestyle histories. Exploring that history informs illness; how clinicians incorporate that history is important to disease management and patient outcomes.
What follows is an overview of comorbidities and MS.
MS and the immune system
MS, for which there is no known cure, permanently disables the body and mind by progressively damaging the myelin sheath that protects axons. It is usually diagnosed in adulthood.
The words chosen to describe MS, from a scientific vantage point, include heterogeneous, complex, and multifaceted. It is likely no one who has, treats, or researches this disease would argue those points. At least 3 journal articles dating back to 2013 all described a discovery about MS as another “brick in the wall.” The latest is a Science Immunology commentary on findings that gut-barrier-protecting Th17 cells could have an evil side, expressing a ligand called dual immunoglobulin domain containing cell adhesion molecule, allowing these cells to infiltrate the blood brain barrier during neuroinflammation.4
So far, 230 loci have been implicated in modulating the risk of MS development.5 That 230 is twice the number found in rheumatoid arthritis6 and more than triple the number of genes and loci linked to psoriasis.7 The genomic map of MS, showing involvement of peripheral immune cells and microglia in susceptibility, resembles a spider web more than genetic cartography.8
One review of the literature listed more than 50 comorbid conditions found in patients with MS. While many of these conditions do not occur more often in those with MS as opposed to those without the disease, a few comorbidities certainly do.9
The comorbidities
As defined, a comorbidity is a co-existing condition not directly related to the primary, or index, disease, which in this case is MS.10 One must wonder if, as the index disease, MS defies this definition, as depression, anxiety, hypertension, hyperlipidemia, and chronic lung disease are frequently found in patients with MS: when combined, depression and anxiety are found in nearly half of patients.11,12
But MS is not dependent on aberrant genes solely for its development. The environmental and lifestyle risk factors linked to an MS diagnosis include childhood obesity, Epstein Barr virus infection (the virus that causes infectious mononucleosis), smoking, and low levels of vitamin D.13,14 A common denominator among virtually all these factors, not unlike the comorbidities themselves, is inflammation.
It is not uncommon for patients with MS to have psoriasis.7,10 Nor is it uncommon for them to have other types of autoimmune diseases, such as inflammatory bowel disease. For patients with MS, the relative risk is increased for developing some other autoimmune diseases including inflammatory bowel disease, psoriasis, and bullous pemphigoid (another skin condition).
Studies of patients with rheumatoid arthritis (RA) have shown how RA is directly or indirectly responsible for the development of other diseases, primarily due to RA’s creation of inflammatory pathways.15 In patients with RA, comorbidities tend to become fewer as the disease progresses. As already discussed, in patients with MS, comorbidities generally increase over time.15,16 As for whether a comorbidity could cause the development of MS, that question has yet to be answered.
Comorbidity specifics
There are a few comorbidities that appear in the literature more than others, with most of them falling into the vascular or the central nervous system. Diseases associated with the vascular system, including hypertension and diabetes, as they accumulate in number, will cause more physical impairment.17 A single vascular comorbidity at diagnosis was associated with a 51% increased risk of early gait disability, while 2 vascular comorbidities were associated with a 228% increased risk.18
Other comorbidities, like chronic obstructive pulmonary disease (COPD), can cause disease to progress at a quicker pace.10 COPD also can increase risk of an earlier death, as can epilepsy.10,16 People with MS, mostly women diagnosed in the prime of their lives, live 6 to 8 fewer years than those without.19
Some coexistent diseases are also linked to a longer delay to MS diagnosis and lower rate of treatment. A large study in Canada showed ischemic heart disease and anxiety were linked with a patient’s lower rate of receiving disease-modifying therapies.9
In time
While not every patient with MS has co-existing disease at the time of diagnosis, it will be highly likely that these patients will have comorbidities as the years pass. In 1 study, researchers found that the prevalence of some comorbidities, like gastrointestinal disorders, thyroid disease, and anxiety, increased as patients aged.20
When reviewing health claims data for patients with inflammatory bowel disease and RA, researchers found a similar risk of depression in both. Health claims data also show patients looking for treatment for anxiety 5 years before an MS diagnosis. Of patients who were not yet diagnosed, 19% had sought help for depression and 11% for anxiety.9
Researchers looked at 2526 patients diagnosed with MS and 9980 controls to compare the risk of developing comorbidities prior to MS diagnosis and after.16 At diagnosis, 22.7% of patients had at least one Charlson comorbidity compared with 16.8% of controls. (The Charlson comorbidity index is a weighted score comprised of several comorbidities. Scores span mild to severe, or 1 to above 5.) 21
Ten years prior to MS diagnosis, out of ~30 diseases, patients with MS were at risk to develop at least 20 of the 30, including various cancers, cardiovascular diseases, thyroid disorders, and neurologic and mental disorders. For the latter, the difference was 34.92% vs 17.87%. In the period after diagnosis, 17.23% of patients had a new comorbidity, as compared to 15.78% in the control population. The change was remarkable in the neurologic and mental disorders; prior to an MS diagnosis, there were no cases of dementia, but that changed post-diagnosis.