Abstract
Background
Comorbidity may be associated with the clinical phenotype of disease, and may affect prognostication and treatment decisions. Using the North American Research Committee on Multiple Sclerosis Registry, we described comorbidities present at onset and diagnosis of multiple sclerosis (MS); and examined whether comorbidities present at onset were associated with clinical course or age of MS symptom onset.
Methods
In 2006, 8983 participants reported their physical and mental comorbidities; smoking status; height; and past and present weight. We compared clinical course at onset and age of symptom onset by comorbidity status.
Results
At MS onset a substantial proportion of participants had physical (24%), or mental (8.4%) comorbidities. The mean (SD) age of MS onset was 31.2 (9.0) years. Vascular, autoimmune, cancer, visual, and musculoskeletal comorbidities were associated with a later age of symptom onset. Among men and women the odds of a relapsing course at onset were increased if mental comorbidities (OR 1.48; 1.08–2.01) were present at symptom onset. In women, gastrointestinal comorbidities (OR 1.78; 1.25–2.52) and obesity (OR 2.08 1.53–2.82) at MS onset were also associated with a relapsing course at onset.
Conclusions
Comorbidity is frequently present at onset of MS and is associated with differences in clinical characteristics.
Keywords: comorbidity, epidemiology, multiple sclerosis, smoking
Introduction
Comorbid conditions and health behaviors may be associated with the clinical phenotype of chronic diseases. In Parkinson’s disease, for example, smokers have a later age of symptom onset, and fewer motor fluctuations and dyskinesias after levodopa treatment than non-smokers.(1) In a cohort of over 1400 patients with multiple sclerosis (MS), current smokers were more likely to have primary progressive MS rather than relapsing forms of MS.(2) Such phenotypic differences may influence prognosis and treatment.
Physical and mental comorbidity are common in multiple sclerosis (MS), affecting more than 50% of individuals.(3) Little is known, however, regarding the association of comorbidity with the clinical characteristics of MS. Previous studies of comorbidity and clinical characteristics focused on comorbid autoantibodies or autoimmune disease, and did not identify any association with comorbidity, but their sample sizes were small.(4–6) The relationships of other types of comorbidities with clinical characteristics are not well elucidated.
We aimed to describe comorbidities present at onset and diagnosis of MS, and to examine whether the type of clinical course differs between patients with and without comorbidity present at the time of MS onset.
Materials And Methods
The methods of this study are detailed elsewhere.(3) Briefly, the NARCOMS Registry is a self-report registry for patients with MS,(7) which is approved by the Institutional Review Board at the University of Alabama at Birmingham. Diagnoses of MS and various clinical characteristics have been validated in a random sample of NARCOMS participants.(8) In October 2006, participants reported physical and mental comorbidities. They indicated the presence or absence of a comorbidity, and if present, the year of diagnosis. We also queried smoking status; alcohol intake; height; and past and present body weight. We restricted eligibility to participants living in the United States with complete data regarding date of birth, age of MS symptom onset, and age of MS diagnosis; and age of symptom onset ≥ 16 years and <60 years (n= 16141).(3) The validity of self-reported diagnoses is variable, being reasonably accurate for well-defined, chronic conditions requiring ongoing care, but less accurate for diseases with less explicit diagnostic criteria.(9, 10) Therefore we classified comorbidities as very likely to be accurately self-reported, moderately likely to be accurately self-reported, and least likely to be accurately reported based on literature review (Table 1).(9–13)
Table 1.
Frequency of physical comorbidities at symptom onset or diagnosis of multiple sclerosis, and mean (standard deviation) duration of these diagnoses prior to the symptom onset or diagnosis of multiple sclerosis
| Comorbidity | Responses to Question n | Affected at MS onset, n (%) | Mean (SD) duration before MS onset (yrs) | Affected at MS diagnosis, n (%) | Mean (SD) duration before MS diagnosis (yrs) |
|---|---|---|---|---|---|
| Very likely to be accurately reported | |||||
| Hypertension | 8581 | 322 (3.8) | 7.4 (7.2) | 688 (8.0) | 7.8 (7.9) |
| Heart disease | 8792 | 63 (0.7) | 6.9 (6.7) | 136 (1.5) | 7.1 (7.5) |
| Diabetes | 8740 | 52 (0.6) | 8.2 (7.7) | 109 (1.2) | 7.6 (8.8) |
| Inflammatory bowel disease | 8779 | 90 (1.0) | 9.8 (8.8) | 140 (1.6) | 12.3 (9.8) |
| Invasive Cancer | |||||
| Breast cancer (women) | 6760 | 15 (0.22) | 6.5 (6.4) | 32 (0.47) | 8.6 (6.7) |
| Colon cancer | 8895 | 4 (0.04) | 15.5 (9.9) | 9 (0.10) | 13.4 (16.7) |
| Rectal cancer | 8893 | 0 | - | 2 (0.022) | 1.0 (1.4) |
| Lung cancer | 8892 | 0 | - | 1 (0.0007) | 0 |
| Moderately likely to be accurately reported | |||||
| Lung disease | 8731 | 429 (4.9) | 15.5 (11.3) | 585 (6.7) | 17.7 (13.4) |
| Hypercholesterolemia | 8427 | 227 (2.7) | 6.0 (6.2) | 555 (6.6) | 6.0 (6.4) |
| Thyroid | 8720 | 223 (2.6) | 9.3 (8.0) | 400 (4.6) | 10.9 (9.7) |
| Peptic ulcer disease | 8736 | 224 (2.6) | 8.5 (7.3) | 340 (3.9) | 12.3 (9.2) |
| Uveitis | 8733 | 44 (0.5) | 7.0 (8.8) | 114 (1.3) | 9.3 (9.3) |
| Cataracts | 8716 | 41 (0.5) | 9.0 (12.8) | 96 (1.1) | 8.6 (11.5) |
| Glaucoma | 8798 | 20 (0.2) | 5.9 (6.9) | 49 (0.56) | 6.7 (7.5) |
| HIV | 8840 | 0 | - | 0 (0) | - |
| Unlikely to be accurately reported or accuracy unknown | |||||
| Anemia | 8672 | 375 (4.3) | 12.9 (9.9) | 518 (6.0) | 15.8 (11.5) |
| Irritable bowel syndrome | 8604 | 297 (3.5) | 7.9 (7.2) | 493 (5.7) | 10.3 ( 8.9) |
| Arthritis | 8581 | 140 (1.6) | 7.0 (6.6) | 353 (4.1) | 8.1 (8.3) |
| B12 deficiency | 8706 | 98 (1.1) | 9.7 (10.1) | 201 (2.3) | 9.2 (11.0) |
| Fibromyalgia | 8805 | 53 (0.6) | 4.5 (4.2) | 190 (2.2) | 6.2 (5.6) |
| Skin cancer | 8568 | 69 (0.8) | 5.4 (6.3) | 125 (1.5) | 7.0 (12.3) |
| Rheumatoid arthritis | 8713 | 55 (1.1) | 10.1 (7.6) | 102 (1.2) | 11.0 (9.8) |
| SLE | 8730 | 18 (0.2) | 11.6 (20.2) | 49 (0.56) | 11.1 (14.9) |
| Kidney disease | 8799 | 31 (0.4) | 14.2 (10.7) | 44 (0.50) | 18.2 (13.6) |
| Liver disease | 8827 | 29 (0.3) | 10.6 (7.2) | 42 (0.48) | 13.6 (9.9) |
| Peripheral vascular disease | 8774 | 22 (0.3) | 7.5 (10.0) | 41 (0.47) | 11.5 (11.4) |
| Sjogren's Syndrome | 8795 | 3 (0.03) | 4.7 (1.5) | 16 (0.18) | 8.6 (7.2) |
| Knee replacement | 8835 | 8 (0.09) | 11.3 (9.7) | 15 (0.17) | 9.5 (9.7) |
| Hip replacement | 8827 | 3 (0.03) | 11.7 (11.7) | 12 (0.14) | 6.1 (8.1) |
Categorical variables are reported as frequency (percent). Continuous variables are reported as mean and standard deviation (SD) or median and interquartile range (IQR). For each comorbidity or health behavior, we report the proportions of participants affected at MS symptom onset and at MS diagnosis. To minimize multiple comparisons, subsequent analyses grouped comorbidities into conceptual categories: physical, mental, vascular, autoimmune, cancer, visual, musculoskeletal, and gastrointestinal (Table 2). Physical comorbidity refers to the presence of any physical comorbidity which was very likely to be accurately self-reported. Participants were categorized according to the presence or absence of comorbidity at onset and diagnosis of MS. The number of participants reporting cancer at MS onset or diagnosis was too small for further evaluation.
Table 2.
Definition of comorbidity categories, and the frequency of NARCOMS participants reporting being affected at onset and diagnosis of multiple sclerosis
| Comorbidity Category | Comorbidities Included | Frequency at Onset (n, %) | Frequency at Diagnosis (n, %) |
|---|---|---|---|
| Vascular | Diabetes, hypertension, heart disease, peripheral vascular disease, hypercholesterolemia | 578 (6.8) | 1199 (14.0) |
| Autoimmune | Autoimmune thyroid disease, uveitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, Sjogren’s disease | 410 (4.7) | 750 (8.7) |
| Musculoskeletal | Fibromyalgia, osteoarthritis, rheumatoid arthritis, systemic lupus erythematosus, hip/knee replacement | 241 (2.8) | 592 (6.9) |
| Gastrointestinal | Peptic ulcer disease, irritable bowel syndrome, inflammatory bowel disease, liver disease | 603 (6.9) | 860 (9.9) |
| Visual | Uveitis, cataracts, glaucoma | 62 (0.78) | 155 (2.0) |
| Non-skin cancers | Lung, breast, colon, and rectal cancers | 19 (0.21) | 44 (0.49) |
| All cancers | Lung, breast, colon, rectal, skin cancers | 70 (0.84) | 168 (1.9) |
We classified each participant’s clinical course as relapsing or progressive at onset. At enrollment, participants report whether they have ever had a relapse, and whether their symptoms have progressed in the absence of relapses. The history of relapses and progression is updated semi-annually. Thus a participant who never reported a relapse at enrollment or on any semi-annual update questionnaire was classified as progressive at onset; all other participants were classified as relapsing at onset.
For stratified analyses, year of symptom onset was categorized as ≤ 1980, 1981–1984, 1985–1989, 1990–1994, 1995–1999, and ≥ 2000 to achieve categories of reasonable size. Age at symptom onset was categorized as ≤ 25, 25 to 39, or ≥ 40 years based on previous work with this cohort.(14) We compared the clinical course at onset between affected and unaffected participants in each comorbidity category using a chi-square or Fisher’s exact test. We compared the age of symptom onset between affected and unaffected groups using a Kruskal-Wallis test; or using unbalanced ANOVA, adjusted for multiple comparisons. To evaluate the independent association between comorbidity and clinical course at onset we used logistic regression; the covariates year of symptom onset and age of symptom onset were represented as indicator variables with the lowest category as the reference group. Race (white versus non-white) was included as a covariate because of possible disease-related differences between races,(15) and education (high school education or less versus more than high school education) was included as a measure of socioeconomic status which was likely to be stable over time. Assumptions of the logistic model were tested using standard methods.(16) Odds ratios and 95% confidence intervals (CI) are reported. All statistical analyses were conducted using SAS V9.1 (Sas Institute Inc., Cary, NC).
Results
As reported previously, 8983 NARCOMS participants responded to the Fall 2006 questionnaire.(3) We initially reported a response rate of 55.5%,(3) but subsequent linkage to the National Death Index determined that 104 non-responders had died, leading to a revised response rate of fifty six percent. Most participants responding to the questionnaire were white (94.3%), women (75.8%), and had a mean (SD) age of 52.7 (10.4) years.(3) Their mean (SD) age of onset was 31.2 (9.0) years and mean (SD) age of diagnosis was 38.2 (9.5) years. One-third of participants (3178) were mildly disabled, while 1067 (11.9%) were moderately disabled, and 4738 (52.7%) were severely disabled.
Comorbidity and health behaviors at onset and diagnosis of MS
At MS onset, 2062 (24.0%) participants had at least one physical comorbidity, of whom 996 (48.3%) participants reported one, 531 (25.8%) reported two, and 535 (25.9%) reported three or more. The most common physical comorbidities were hypertension (3.8%), lung disease (4.9%), hypercholesterolemia (2.7%), anemia (4.3%), and irritable bowel syndrome (3.5%) (Table 1). At onset 698 (8.4%) participants reported a mental comorbidity, with depression being most frequent (Table 3). Based on their maximum reported weight in the surrounding years, nearly 50% of participants were overweight (2175) or obese (1652) at MS onset. Slightly less than 50% of participants reported ever smoking (4335), and 3249 (38.7%) actively smoked at symptom onset.
Table 3.
Frequency of mental comorbidities at onset and diagnosis of multiple sclerosis, and mean duration of these diagnoses prior to the onset and diagnosis of multiple sclerosis
| Comorbidity | Responses to Question, n | Affected at onset, n (%) | Mean (SD) duration before onset (yrs) | Affected at diagnosis, n (%) | Mean (SD) duration before diagnosis (yrs) |
|---|---|---|---|---|---|
| Depression | 8337 | 613 (7.4) | 6.0 (6.6) | 1431 (17.2) | 6.6 (7.5) |
| Anxiety | 8570 | 233 (2.7) | 5.8 (6.0) | 534 (6.2) | 6.7 (7.2) |
| Bipolar disorder | 8806 | 44 (0.5) | 7.0 (6.1) | 86 (1.0) | 9.0 (7.8) |
| Schizophrenia | 8846 | 5 (0.06) | 7.8 (8.8) | 7 (0.08) | 10.1 (8.0) |
At diagnosis, 3141 (35.0%) participants had at least one physical comorbidity, of whom 1682 (53.6%) had one comorbidity, 774 (24.6%) had two, and 685 (21.8%) three or more. The most common individual physical comorbidities were the same as those at MS onset (Table 1). Eighteen percent (n = 1537) participants reported a mental comorbidity (Table 3). At diagnosis, 4587 (53.0%) participants had a history of smoking, of whom 2747 (59.9%) were actively smoking. Fifty percent of participants were overweight (2373, 26.4%) or obese (2138, 23.8%). Slightly less than half of participants (4837) reported neither physical nor mental comorbidities at diagnosis, while 638 (7.4%) reported mental comorbidity only, 2240 (26.0%) reported physical comorbidity only, and 899 (10.4%) reported both. Subsequent results are discussed by comorbidity category (Table 2).
Comorbidity and age of MS symptom onset
The reported age of symptom onset differed according to the presence or absence of physical comorbidity at MS onset. As compared to participants without the comorbidity at MS onset, the mean age of MS symptom onset was higher in participants with any vascular, autoimmune, visual, gastrointestinal, or musculoskeletal comorbidity (Table 4). As the number of comorbidities present in the comorbidity category increased, the mean age of MS onset increased except for gastrointestinal comorbidity where the reverse occurred (Table 4, p<0.0001). The mean age of MS symptom onset did not differ between participants who did (39.1 (8.5)) and did not (38.2 (9.5), p=0.53) have mental comorbidities at MS onset. Stratification analyses did not show an interaction effect between the number of mental comorbidities and number of physical comorbidities at MS onset on age at symptom onset (data not shown).
Table 4.
Mean (standard deviation) age of multiple sclerosis (MS) symptom onset among NARCOMS participants according to the number of comorbidities reported at MS onset in a physical comorbidity category (n = 8893)
| Comorbidity Category | Number of Comorbidities Reported |
|||
|---|---|---|---|---|
| 0 | 1 | 2 | 3 | |
| Vasculara | 30.7 (8.8) (n= 8403) | 36.9 (9.0) (n= 489) | 42.0 (9.1) (n=76) | 45.5 (7.5) (n= 13) |
| Autoimmunea | 31.0 (9.0) (n= 8572) | 35.1 (9.3) (n=388) | 35.9 (7.7) (n= 21) | 39.0 (15.6) (n= 2) |
| Visuala | 31.1 (9.0) (n= 8920) | 36.6 (10.6) (n=62) | 25.0 (−)(n= 1) | - |
| Gastrointestinala | 31.0 (9.0) (n=8420) | 33.3 (8.8) (n= 490) | 34.7 (7.5) (n=69) | 32.0 (6.2) (n=4) |
| Musculoskeletala | 31.1 (9.0) (n=8742) | 35.3 (9.6) (n= 224) | 41.7 (9.3) (n=16) | 53.0 (−)(n= 1) |
Vascular = diabetes, hypertension, heart disease, peripheral vascular disease, hypercholesterolemia; Autoimmune = autoimmune thyroid disease; uveitis; systemic lupus erythematosus; rheumatoid arthritis; inflammatory bowel disease; Sjogren’s disease; Gastrointestinal = peptic ulcer disease; irritable bowel syndrome; inflammatory bowel disease, liver disease; Musculoskeletal = fibromyalgia, arthritis, rheumatoid arthritis, systemic lupus erythematosus, hip replacement, knee replacement; Visual = uveitis, cataracts, glaucoma Means compared between groups using unbalanced ANOVA, adjusted for sex, race, education, and adjusted for multiple comparisons; a- P for linear trend age of onset ≤ 0.0001
Never smokers had a mean age of symptom onset of 31.1 (9.0) years which did not differ from the mean age of onset (31.2 (9.0) years, p = 0.65) in ever smokers. Overweight or obese participants had a later mean age of symptom onset (31.9 (9.2) years) than participants with a normal weight (30.5 (8.9) years, p<0.0001). The ages of symptom onset did not differ between overweight (p=0.69) and obese participants (p=0.23).
Comorbidity and health behaviors at onset, and clinical course
Nearly 90% (7602) of participants reported a relapsing course at MS onset. Because the stratified analysis suggested sex-related differences regarding comorbidity and course (data not shown), we included interaction terms between sex and comorbidity in our multivariable logistic models. We identified interactions between sex, and gastrointestinal comorbidities and obesity. After adjustment for age of symptom onset, year of symptom onset, sex, and race, both men and women had increased odds of a relapsing course at onset if they reported mental (OR 1.48; 1.08–2.01) comorbidities. Among women, gastrointestinal comorbidities (OR 1.78; 1.25–2.52) and obesity (OR 2.08 1.53–2.82) at MS onset were also associated with a relapsing course at onset. Among men, neither gastrointestinal (OR 1.33; 0.76–2.33) comorbidities nor obesity (0.95; 0.67–1.34) were independently associated with a relapsing course at onset.
To determine if there was a dose-response association between the number of physical comorbidities at MS onset and clinical course at onset, we created a logistic model including the number of comorbidities as a linear term. After adjustment for sex, year of symptom onset, and age of symptom onset, the odds of reporting a relapsing course at onset increased 22% per comorbidity (OR 1.22; 1.11–1.34).
Sensitivity Analyses
Our results did not change when we restricted analyses to participants with an age of symptom onset between 16 and 50 years. Similarly, when we removed comorbidities which were classified into more than one comorbidity category (e.g. autoimmune diseases could also be classified into musculoskeletal categories in some cases) from those categories, our results did not change. To account for the possibility that patients with comorbid diagnoses of SLE or Sjogren’s disease may be misdiagnosed with MS we excluded them and repeated the analyses; the results did not change significantly.
Discussion
Even when MS is newly diagnosed a substantial proportion of affected persons have physical and mental comorbidities. Patients with MS often have a history of smoking, and overweight or obesity. We evaluated whether comorbidities present at MS onset are associated with differences in clinical characteristics. Few previous studies assessed the association of comorbidity and MS phenotype, and most focused on autoimmune disease.(4–6) Two studies, each with fewer than 200 participants, reported that MS patients with autoimmune features or thyroid disease did not differ from MS patients without such features with respect to clinical characteristics.(4, 6) Another study of 105 patients found that persons with onset over age 20 years or progressive MS were more likely to be autoantibody positive than those with onset before age 20 years or relapsing MS;(17) specific autoimmune diseases were not evaluated.
Our findings suggest that some comorbid diseases and health behaviors (mental, gastrointestinal, obesity) are associated with whether patients present with a relapsing or primary progressive course at onset. Recent studies suggest that the female to male ratio is increasing in MS, that the age of MS symptom onset is shifting, and that relapsing MS is becoming more common than primary progressive MS.(18) The timescale of these changes is consistent with a changing environmental factor; our findings raise the possibility that comorbid diseases and health behaviors could be a relevant factor. A recent analysis of the Nurses’ Health Study cohorts suggested that obesity at age 18 years was associated with a more than two-fold increased risk of MS.(19) A Danish study suggested that the psychological stress of the death of a child increased the risk of developing MS, and depression is known to induce changes in immune function.(20, 21) If these conditions influence the risk of disease, they could potentially influence the phenotype of disease too. As comorbidity continues to increase in the general population, this will become an increasingly important issue. Our findings also suggest that sex modifies the association of comorbidity with clinical course, consistent with reported sex-related differences in MS, including differences in susceptibility, severity, and immune responses.(22)
Vascular, autoimmune, visual, and musculoskeletal comorbidities were associated with a later age of symptom onset. These associations showed a dose response relationship; that is, the mean age of symptom onset increased as the number of comorbidities in the comorbidity category increased. Considered at the population level these changes are substantial. Several possible explanations exist for the findings regarding age of symptom onset. First, greater comorbidity at later ages of initial symptom onset may simply reflect expected increases in comorbidity with increasing age. Second, comorbidity could delay the onset of MS. Third, comorbidity might delay the recognition of MS, because symptoms were attributed mistakenly to another condition.(23) Regardless, patients with a later age of symptom onset differ from those with an earlier age of onset; they are more likely to have comorbid diseases and health behaviors which may influence prognosis and complicate treatment. Other studies suggest that the presence of comorbid vascular disease, musculoskeletal comorbidities and smoking in patients with MS are associated with increased disability progression or functional decline.(24, 25) Many clinical trials in MS exclude individuals with severe comorbidities or substance use disorders,(26, 27) thus the safety, tolerability and effectiveness of available medications is not known in such patients. In obsessive compulsive disorder, for example, treatment response to cognitive behavioral therapy is reduced in patients with comorbid anxiety or personality disorders.(28) Our findings suggest that the findings of clinical trials excluding patients with comorbidities should be generalized cautiously to patients with comorbidities. Precedents exist for comorbidity-based differences in disease management in other conditions, including hypertension, community-acquired pneumonia, and prostate cancer.(29–31)
Some of this study’s limitations were discussed previously.(3) The response rate of 56% is less than desired but compares favorably with that in published surveys.(32) Non-responders differed from responders thus our findings may not generalize as well to African Americans and persons of lower socioeconomic status. Participants in the NARCOMS Registry are volunteers but constitute a large, diverse population with characteristics similar to those reported for MS patients from the National Health Interview Survey.(33) Comorbidity data were self-reported thus misclassification was possible, and we do not know whether this misclassification varied according to the length of the period between the onset of the comorbidity and when participants were surveyed. However, such misclassification is unlikely to explain our findings because it would tend to reduce our ability to detect an association between comorbidity and clinical characteristics. Further, evaluation of the comorbidity questionnaire used in this study in 400 participants suggests that patients with MS accurately report common physical and mental comorbidities when compared to medical records review.(34) Clinical course at onset was self-reported, but prior work with this cohort showed strong agreement between self-report clinical course and the clinical course reported by the treating physician.(35) For some participants the year of diagnosis for a particular comorbidity was missing; exclusion of those participants from the analysis is a potential source of bias, although the amount of missing data is too small to explain our findings.
Comorbid conditions and adverse health behaviors are often present when MS is diagnosed, and are associated with differences in the age of symptom onset, age of diagnosis, and type of clinical course. Further research is needed to understand the associations between comorbidity and MS, including the effects on treatment and outcome.
Acknowledgments
Supported in part by the National Institutes of Health, National Institute of Child Health and Human Development, Multidisciplinary Clinical Research Career Development Programs Grant K12 HD049091. Supported in part by the Consortium of Multiple Sclerosis Centers, and a Foundation of the CMSC Grant from EMD Serono Inc.
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