The current understanding of multiple sclerosis (MS) as a progressive and long-term disabling disease has been based on studies of clinical course of the disease in areas of high disease prevalence [
Although Weinshenker et al. (1989) have reported that approximately 50% of relapsing-remitting cases required an unilateral support to walk within an average of 15 years [
An increasing number of studies have identified the population ancestry as a risk factor, not only for susceptibility to MS but also for clinical progression. Disease outcomes have been shown to be poorer in patients with African ancestry [
The aim of this study was to describe and analyse the secondary progression of RRMS in a tropical region with higher proportions of African descents, taking into consideration the influence of clinical characteristics and demographic as ancestry.
We conducted a study of survival on a subset of patients with RRMS [
From the registry of all patients with RRMS according to McDonald et al. Criteria [
Clinical onset was defined as the year of the first relapse. The observation period concluded with the last recorded evaluation in or before December 31, 2010.
Information on relapses, recovery, disability, and progression scores was obtained from the records of follow-up visits.
Cases with an initial optic spinal manifestation were reviewed and specific criteria [
Relapse was defined as the presence of acute neurological symptoms or worsening of preexisting symptoms for longer than 24 hours and followed by partial or complete remission [
Initial clinical manifestations were categorised by functional system (FS): pyramidal, cerebellar, sensory, visual, brainstem, sphincter, and psychiatric. Disability scores were measured with the Kurtzke Expanded Disability Status Scale (EDSS) [
The clinical course was classified as benign if the EDSS score was 3 or less after ten years of disease [
The secondary progression (progressive phase onset of the disease or secondary progressive multiple sclerosis (SPMS)) was defined as a maintained increase in EDSS score not attributed to a relapse that continued for six months or longer with no improvement or progressive worsening with each assessment.
The time to secondary progression was investigated in relation to the following factors: gender (male versus female); ancestry: (African descent—if there were blacks in the family as far back as the third generation versus white); age at onset of disease (less than 30 years versus 30 years or more); type (pyramidal, cerebelar, sensory, brain stem, visual, sphincter, and mental); number of initial neurological manifestations (one versus two or greater than two); number of relapses in the first year of disease (until two versus more than two); first interattack interval (until two years versus more than two years); recovery from the first relapse: residual deficits absent versus present; immunosuppressive or immunomodulatory therapy: used versus not used.
The
Statistical significance was set at
Of 623 patients with MS in the registry, 553 (88%) were diagnosed with RRMS [
Demographic and clinical characteristics for the cases are represented in Table
Initial clinical factors and progression characteristics according to gender and ethnicity.
Characteristics | General | Female | Male | African descent | White |
---|---|---|---|---|---|
|
150 | 119 (79.3) | 31 (20.7) | 33 (22.0) | 117 (78.0) |
Age at disease onset | |||||
Mean ± SD |
|
|
|
|
|
Involved functional systems (FS) at onset | |||||
1 FS (%) | 104 (69.3) |
86 (72.3) |
18 (58.1) |
23 (69.7) |
81 (69.2) |
≥2 FS (%) | 46 (30.7) | 33 (27.7) | 13 (41.9) | 10 (30.3) | 36 (30.8) |
Initial symptoms of MS (%) | |||||
Pyramidal | 55 (36.3) | 39 (32.8) | 16 (51.6) | 14 (42.4) | 41 (35.0) |
Cerebellar | 22 (14.7) | 15 (12.6) | 7 (22.6) | 3 (9.1) | 19 (16.2) |
Visual | 23 (15.3) | 19 (16.0) | 4 (12.9) | 4 (12.1) | 19 (16.2) |
Sensory | 67 (44.7) | 52 (43.7) | 15 (48.4) | 17 (51.5) | 50 (42.7) |
Brainstem | 33 (22.0) | 28 (23.5) | 5 (16.1) | 6 (18.2) | 27 (23.1) |
Sphincter | 6 (4.0) | 4 (3.4) | 2 (6.5) | 1 (3.0) | 5 (4.3) |
Psychiatric | 2 (1.3) | 2 (1,7) | 0 | 1 (3.0) | 1 (0.9) |
First interval between exacerbations, years | |||||
Short (≤2 years) | 85 (56.7) | 64 (53.8) | 21 (67.7) | 19 (57.6) | 66 (56.4) |
Long (>2 years) | 65 (43.3) | 55 (46.2) | 10 (32.3) | 14 (42.4) | 51 (43.0) |
Recovery from 1st exacerbation | |||||
Complete recovery | 124 (82.7) | 100 (84.0) | 24 (77.4) | 24 (72.7) | 100 (85.5) |
Incomplete recovery | 26 (17.3) | 19 (15.9) | 7 (22.6) | 9 (27.2) | 17 (14.5) |
Relapses in the first year of disease (%) | |||||
1 exacerbation | 123 (82.0) | 98 (82.4) | 25 (80.6) | 24 (72.7) | 99 (84.6) |
≥2 exacerbations | 27 (18) | 21 (17.6) | 6 (19.4) |
9 (27.3) | 18 (15.4) |
Benign disease (%) | |||||
Yes | 120 (80.0) | 97 (81.5) | 23 (74.2) | 20 (60.6) | 100 (85.5)* |
No | 80 (20) | 22 (18.5) | 8 (25.8) | 13 (39.4) | 17 (14.5) |
Malignant disease (%) | |||||
Yes | 6 (4.0) | 4 (3.4) | 2 (6.5) | 4 (12.1)* | 2 (1.7) |
No | 144 (96) | 115 (96.6) | 29 (93.5) |
29 (87.9) | 115 (98.3) |
Secondary progression (%) | |||||
Yes | 59 (39.3) | 45 (37.8) | 14 (45.2) | 17 (51.5) | 42 (35.9) |
No | 91 (60.7) | 74 (62.2) | 17 (54.8) | 16 (48.5) | 75 (64.1) |
FS: functional system of Kurtzke’s EDSS scale; benign disease: at 10 years of disease EDSS 3 or less; malign disease: at 5 years of disease EDSS 6 or more; *
The majority of patients were female (79%) and Caucasian (78%). In most patients, the age of disease onset was between the third and fourth decades of life.
Most patients (82%) had one relapse in the first year of disease, and of those most experienced a full recovery (83%).
The initial clinical condition was characterised by the involvement of one functional system in two-thirds of the patients, and sensory manifestations were the most common. Stratification by gender and ethnicity showed a trend towards predominance of motor symptoms in male patients (
The time interval between the first and second relapses was no more than two years in more than half of the patients.
No significant differences in initial clinical characteristics were noted when controlling for gender and ethnicity.
Approximately 40% of patients, with a mean age of 44 years and an average duration of disease of 13 years, advanced to the progressive form of MS. A higher frequency of men (45.2%) and of African descent patients (51.5%) progressed to the secondary progressive form, without statistical significance. No significant difference was observed in the mean age at the onset of progression with respect to gender or ethnicity.
Approximately 80% of patients at ten years of the disease had benign MS. A larger number of Caucasians were significantly more often (85%, IC95%: 78.2%–92.0%;
Disability was significantly different between groups of ancestry: EDSS median scores were higher in African descent patients than in non-African descent at five years of the disease (1.9 versus 0,
On average, patients waited five to six years before receiving a diagnosis. The shortest period between disease onset and diagnosis was one month and the longest was 29 years.
Over 70% of patients (111/150) were treated with disease-modifying drugs (DMDs) for at least 3 months, including immunomodulators (102/111) and immunosuppressants (9/111). The average time before initiating therapy was greater than ten years in 54% of the patients and ranged from one to 38 years, with no significant differences with regard to gender. African descent and non-African descent patients were diagnosed and treated after medians of time very close (Table
Times to diagnosis and treatment according to ancestry.
Ancestry | Time of disease to diagnosis | Time of disease to start treatment |
---|---|---|
White | ||
Median | 4.0 | 10.0 |
Minimum | 0.10 | 0.60 |
Maximum | 29.0 | 38.0 |
Afro | ||
Median | 3.0 | 8.0 |
Minimum | 0,50 | 1,00 |
Maximum | 28.0 | 41.0 |
|
|
|
Total | ||
Median | 3.5 | 10.0 |
Minimum | 0,10 | 0.60 |
Maximum | 29.0 | 41.0 |
There was no statistically significant difference between the genders with respect to the amount of time before the progression of disease (
African descent patients reached the progressive phase more quickly than non-African descent (11.0 years versus 15.0 years,
In patients who developed MS when they were 30 years and older, the time taken to reach the secondary progression was more rapid than in patients who developed MS when they were younger (14.0 years versus 17.0 years,
Similarly, patients with first interattack interval less than two years reached the secondary progression of the disease more rapidly (13.0 versus 17.5 years,
Patients who experienced first relapse that did not fully remit presented more short time to progression (15.0 years versus 11.0 years,
The time to reach disease progression was significantly less in patients who had more than one relapse in the first year of disease (11.7 versus 17.6 years
Cox logistic regression was performed to assess the effect of ancestry and other initial clinical factors on time to the progressive phase onset of the disease (Table
Multiple Cox regression survival analysis: risk of reaching progression according to ethnicity and clinical features at the onset of disease.
Outcome/variable | Risk | 95% CI |
|
---|---|---|---|
Progression | |||
African descent | 2.0 | 1.1–3.4 | 0.02 |
30 years of age or older at onset | 2.0 | 1.1–3.3 | 0.02 |
2 or more exacerbations during the first year | 2.3 | 1.2–4.3 | 0.009 |
Survival curves (a), (b), and (c) represent the median time to reach progression phase, respectively, according to the ancestry, age at onset of the disease, and the number of relapses in the first year of the disease.
For the patients who reached the secondary progressive phase of MS, the use of DMD had no significant effects on median times in the Kaplan-Meier curves or on the risk for progression (25.5 years versus 29 years,
Considering the scarcity of longitudinal studies and prognosis in Latin America, the current study is the first to analyze the influence of demographic and clinical factors on the survival of RRMS patients of mixed ethnicity. The time to conversion in secondary progressive MS was analysed in 150 patients with more than 10 years of illness which remained in a followup on a reference centre for the treatment of MS. Kremenchutzky et al. (2006) have suggested that the probability of and time to progression have been poorly explored despite having profound relevance [
The selection of cases with more than ten years of evolution was provided for sufficient time to observe both benign and malignant trajectories of the disease course. Moreover, this time frame would theoretically minimise the possible influence of DMD because the distribution of these drugs in our country began in the last decade. This is supported by the average time of 11 years before beginning DMD treatment. Another observation is that the average time to diagnosis of MS and to the initiation of treatment did not differ between African descendants and Caucasians, which suggests that the potential influences of socioeconomic factors related to race did not affect our results. The use of DMD did not significantly affect the time to disease progression. The results obtained from clinical trials with immunomodulatory [
Anatomopathological studies indicate that the biological mechanisms responsible for neurodegeneration and disability are distinct from those that cause inflammation and relapses [
A difference in the speed to long-term disability outcomes between men and women has been identified, with a worse prognosis for male patients [
Later age at disease onset is another factor that has been described as a risk factor for progression [
The presence of residual deficits after the first neurological manifestation [
The poorer outcomes in individuals of African ancestry could suggest the participation of non-HLA genes; as an example is the polymorphisms in
The intervals of time from the onset of the disease until the onset of the progressive phase were influenced by initial clinical characteristics and mainly by ancestry, the latter being a biological variable intrinsic to the patient, not the disease. Both conditions, demographic and clinical, are present at the onset of the disease and should be considered together with the therapeutic window in intervention strategies. The recognition of the role of ancestry on prognosis also serves to stimulate genetics and pharmacogenomics research that may clarify the poorly understood neurodegenerative component of MS.